KR20070113255A - Novel compounds - Google Patents

Abstract

Novel substituted 2,4,8-trisubstituted 8H-pyrido[2,3-d]pyrimidin-7-one containing compounds and compositions, and their use use in therapy as CSBP/RK/p38 kinase inhibitors.

Description

New compound {NOVEL COMPOUNDS}

The present invention relates to novel compounds and their use as pharmaceuticals (particularly p38 kinase inhibitors) for the treatment of certain diseases and conditions.

Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of cell surface receptors (eg, protein tyrosine kinases or seven transmembrane G-protein coupled receptors), protein kinases and phosphatase are essential to further signal the cell along with phospholipase. Configure the means of operation (Marshall, JC Cell, 80, 179-278 (1995)). Protein kinases can be classified into five classes, two of which are whether the enzyme phosphorylates its substrate (s) on specific tyrosine (s) residues or on serine / trionine (s) residues. And tyrosine kinases and serine / threonine kinases according to (Hunter, T., Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T .; Sefton, BM; eds. Vol. 200, Academic Press; San Diego, 1991].

Three major related intracellular pathways, mitogen-activated kinases or MAPKs are currently understood to convert signals from a number of extracellular stimuli such as environmental stresses, infectious agents, cytokines and growth factors. MAPKs are active in a variety of cellular functions (eg, translocation and activation of transcription factors that control the transcription of effector molecules such as cytokines, COX-2, iNOS); activity of downstream kinases affecting transcription of mRNA; And cell cycle pathways through the transcription or modification of enzymes. One of these three major pathways is called the p38 MAPK pathway, which is referred to as the isotype p38α, which is expressed overall in most cell types. The role of p38 in various functions, particularly in relation to inflammatory responses, has been demonstrated through a number of in vitro and in vivo studies using selective p38 inhibitors. These functions have been extensively reviewed, and an overview of them can be found in Nature, Kumar, S. Nature Rev. Drug Discovery, 2: 717 (2003).

Extracellular stimulation as described above occurs in a number of chronic diseases that are currently understood to have a common intrinsic symptom called inflammation in pathological physiology terms. Environmental damage or local cell damage activates cellular response pathways including p38 and the like, followed by local cells producing cytokines and chemokines, followed by lymphocytes such as neutrophils and other granulocytes. The result of the secondary response is the result of additional lymphocytes, such as additional phagocytes or cytotoxic T cells, participating in the response, and thus finally a suitable immune response is initiated through activation of the T cells. It is not yet fully understood how the acute inflammatory response is a chronic reaction resulting in diseases such as rheumatoid arthritis (RA), atherosclerosis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD) and the like. However, the character of inflammation is recognized to apply to the majority of chronic diseases, and pathways such as the p38 pathway are believed to be responsible for the onset of inflammatory disease.

For example, atherosclerosis is considered a chronic inflammatory disease, which occurs in response to damage of the vessel wall and is characterized by the development of complexes of obstructive and thrombotic atherosclerosis. The etiology of such damage is generally endothelial dysfunction (reduction of bioavailable NO), adhesion molecule expression, adhesion and infiltration of leukocytes, production of cytokines and growth factors, accumulation of afferent cells, expansion of extracellular lipids and matrix, matrix It is associated with the activation of metalloproteases (MMP) and proliferation of vascular smooth muscle cells.

The discovery of p38 (originally named CSBP, now named p38; targets of the compounds in which isotypes p38α and p38β are described) provided the mechanism of action of the anti-inflammatory compound family in which SK & F 86002 is a typical example. Such compounds inhibit the synthesis of IL-1 and TNF in human monocytes at concentrations in the low uM range (Lee, et al., Int. J. Immunopharmac. 10 (7), 835 (1988)). , An animal model refractory to cyclooxygenase inhibitors (Lee; et al., Annals NY Acad. Sci., 696, 149 (1993)).

The mechanism by which stress signals (bacterial and viral infections, pre-inflammatory cytokines, oxides, UV light and osmotic stress) activate p38 is through activation of kinases located upstream from p38, which in turn is at threonine 180 and tyrosine 182 Phosphorylation of p38 activates p38. MAPKAP Kinase-2 and MAPKAP Kinase-3 have been identified as downstream substrates of CSBP / p38, which in turn phosphorylates the heat shock protein Hsp27 and other substrates. Additional downstream substrates known to be phosphorylated by p38 include kinases (Mnk1 / 2, MSK1 / 2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB). Many signaling pathways that require the transformation of stress stimuli have not yet been identified, but it has been shown that a number of substrates for p38 listed above are involved (Cohen, P. Trends Cell Biol., 353-361). (1997) and Lee, JC et al., Pharmacol. Ther. Vol. 82, nos. 2-3, pp. 389-397, 1999). There is also new evidence that p38 is involved in regulating the activity of the NF-κB signaling pathway through its role in histone phosphorylation or acetylation or by reducing the transcriptional capacity of the NF-κB complex (Saccini, S. Nature Immunol). , 3: 69-75, (2002); Carter, AB et al., J Biol Chem 274: 30858-63 (1999). Finally, the role of p38 in the generation of responses to IFN through activation of type I IFN receptors is described (Platanias, Pharmacol. Therap. 98: 129-142 (2003)). Activation of p38 is involved in the regulation of transcription of the gene through modification of specific transcription factors that bind to the promoter component of the IFN sensitive gene. Direct phosphorylation of STAT by p38 has not been clearly demonstrated.

p38 kinase inhibitors (e.g., SK & F 86002 and SB-203580), in addition to inhibiting upregulation of IL-1 and TNF in response to inflammatory stimuli, are present in IL-6, IL-8 in many different cell types. It is effective in reducing the synthesis of a wide variety of pro-inflammatory proteins including, GM-CSF, RANTES and COX-2. Inhibitors of p38 kinase also inhibit TNF-induced expression of VCAM-1 on endothelial cells, TNF-induced phosphorylation and activation of cytosolic PLA2, and IL-1-stimulated synthesis of collagenase and stromelysin It turned out. These and additional data demonstrate that p38 is involved in amplifying cytokine synthesis in response to stress as well as the signaling of generated cytokines (a review of CSBP / P38 kinases is described in Cohen, P. Trends Cell Biol). , 353-361 (1997).

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are important inflammatory cytokines produced by various cells such as monocytes, macrophages and smooth muscle cells. IL-1 has been demonstrated to mediate a variety of biological activities that are thought to be important for other physiological symptoms such as immunomodulation and inflammation (see, eg, Dinarello et al., Rev. Infect. Disease, 6, 51 ( 1984). Many known biological activities of IL-1 include activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and inhibition of plasma iron levels.

There are a number of disease states in which the production of excessive or upregulated IL-1 is associated with exacerbation and / or induction of the disease. Such disease states include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, inflammatory response or inflammatory bowel disease induced by other acute or chronic inflammatory disease states such as endotoxins; Tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. In addition, signs are associated with IL-1 activity on diabetes and pancreatic β cells (review of biological activity due to IL-1 is described in Dinarello, J. Clinical Immunology. 5 (5), 287-297 (1985) ]).

The production of excessive or upregulated TNF may include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms; Sepsis, sepsis shock, toxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host response, Allograft rejection, infections such as fever and myalgia from influenza infection, cachexia associated with infection or malignant tumor, cachexia accompanying AIDS, AIDS, ARC (AIDS-related complications), keloid formation, scars It is involved in the mediation or exacerbation of many diseases including tissue formation, Crohn's disease, ulcerative colitis or fever.

Inflammatory diseases are also characterized by an increase in IL-6 and C-reactive protein (CRP), both of which are sensitive to inhibition by p38 inhibitors. Stimulation of IL-6 by CRP production is directly inhibited by p38 inhibitors in human vascular endothelial cells, and CRP is produced by hepatocytes in response to IL-6. CRP is considered a major risk factor for cardiovascular disease (Circulation 2003.107: 363-369) and may be an important independent risk factor for chronic obstructive pulmonary disease (Circulation 2003.107: 1514-1519). IL-6 is also upregulated in endometriosis (Bedaiwy et al., 2002, Human Reproduction 17: 426-431; [Witz, 2000, Fertility and Sterility 73: 212-214]).

Interleukin-8 (IL-8) and RANTES are chemotactic factors produced by several cell types, including monocytes, fibroblasts, endothelial cells, epithelial cells, neutrophil cells and T cells. Chemokine production is induced by pro-inflammatory stimuli such as IL-1, TNF or lipopolysaccharide (LPS), or viral infection. IL-8 stimulates a variety of functions in vitro. It has been found to exhibit chemical affinity for neutrophils, T-lymphocytes and basophil leukocytes. It also induces histamine release from basophilic leukocytes obtained in both normal and atopic individuals as well as lysosomal enzyme release and respiratory release from neutrophils. IL-8 has also been found to increase the surface expression of Mac-1 (CD11b / CD18) on neutrophils without re-synthesizing the protein, thus contributing to increased adhesion of neutrophils to vascular endothelial cells. Many diseases are characterized by extensive neutrophil infiltration. Compounds that inhibit IL-8 production would be beneficial for symptoms associated with increased IL-8 production, such as chronic obstructive pulmonary disease. RANTES is produced by cells such as epithelial cells and airway smooth muscle cells in response to infection or cytokine stimulation. It mainly shows chemical affinity for T cell subtypes and blood-derived monocytes.

IL-1, TNF and other cytokines affect a wide variety of cells and tissues, and these cytokines as well as other leukocyte derived cytokines are important as central inflammatory mediators of a wide variety of disease states and symptoms. Inhibition of the cytokines is beneficial for controlling, reducing and alleviating the plurality of disease states.

In addition to p38 signaling involved in the production of IL-1, TNF, IL-8, IL-6, GM-CSF, COX-2, collagenase and stromelysin, signal transduction via CSBP / p38 is the same. Required for effector function of pro-inflammatory proteins and some of many other proteins. For example, growth factors such as VEGF, PDGF, NGF transmit signals through surface receptors, which in turn activate cellular signaling pathways including p38 MAPK (Ono, K. and Han, J., Cellular Signaling, 12, 1-13 (2000); Kyriakis, JM and Avruch, J. Physiol Rev 81: 807-869 (2001). TGFχ (a key molecule in the control of inflammatory responses) also activates p38 as TGFβ receptors participate in the response. The involvement of CSBP / p38 in multiple stress-induced signal transduction pathways further supports the potential utility of CSBP / p38 in the treatment of diseases or chronic inflammation resulting from activation of an overly destructive immune system. This expectation is supported by the effective and diverse activities described for CSBP / p38 kinase inhibitors (Badger, et al., J. Pharm. Exp. Thera. 279 (3): 1453-1461, (1996)); Griswold, et al., Pharmacol. Comm. 7, 323-229 (1996); Jackson, et al., J. Pharmacol. Exp. Ther. 284, 687-692 (1998); Underwood, et. al., J. Pharmacol. Exp. Ther. 293, 281-288 (2000); Badger, et al., Arthritis Rheum. 43, 175-183 (2000)).

Chronic inflammation is also characterized by the progress of remodeling and repair of affected tissue, which in some cases causes excessive fibrous tissue. The role of p38 MAPK in fibrosis is supported by the discovery that the enzyme mediates the signaling of transforming growth factor β (TGF-β) on the marker of fibrosis and protein. For example, TGF-β has been shown to increase the kinase activity of p38 MAPK through TGF-β activated kinase TAK-1 (Hanafusa et al., 1999, J. Biol. Chem. 274: 27161- 27167]). In addition, the p38 inhibitor SB-242235 inhibits the increase in TGF-β-induced fibronectin and thrombospondine (Laping et al., 2002, Molec. Pharmacol. 62: 58-64). These results show that p38 MAPK is a key signaling intermediate for the effect of pro-fibrotic cytokine TGF-β on the extracellular matrix and marker components of fibrosis.

p38 also serves to direct cell survival and apoptosis in response to various stimuli. Survival and apoptosis can both be p38 regulated depending on stimulation and cell type (Morin and Huot, Cancer Research. 64: 1893-1898 (2004)). For example, TGF-β can stimulate apoptosis in murine hepatocytes through activation of gadd45b (a protein involved in cell cycle control) in the p38-mediated process (Yoo et al., J Biol. Chem. 278: 43001-43007, (2003)]. In different reaction pathways, UV-stress can activate p38 to promote apoptosis of damaged cells. p38 has also been shown to enhance the survival of lymphocytes, including neutrophils and CD8 + T cells, in response to stress.

There is still a need in the art for compounds that are cytokine inhibitory anti-inflammatory drugs, ie compounds capable of inhibiting CSBP / p38 / RK kinase. The present invention relates to novel compounds that are inhibitors of such p38 kinases.

Summary of the Invention

The present invention provides novel compounds of formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1, And pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof; And compounds of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B, and B1, and pharmaceuticals thereof A pharmaceutical composition comprising an acceptable salt, solvate or physiologically functional derivative, and a pharmaceutically acceptable diluent or carrier.

The present invention provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, to a mammal in need of treatment for CSBP / RK / p38 kinase mediated disease. A method of treating CSBP / RK / p38 kinase mediated disease in said mammal comprising administering a compound of VIIIa, IX, IXa, A, A1, B and B1.

The present invention also provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, to a mammal in need of inhibiting cytokines to treat cytokine mediated diseases. A method of treating cytokine mediated diseases by inhibiting cytokines in said mammal comprising administering a compound of VIII, VIIIa, IX, IXa, A, A1, B and B1.

In addition, the present invention provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, to a mammal in need of inhibition of the production of IL-1. A method for inhibiting the production of IL-1 in said mammal comprising administering a compound of VIIIa, IX, IXa, A, A1, B and B1.

In addition, the present invention provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, in mammals in need of inhibition of the production of IL-6, A method of inhibiting the production of IL-6 in said mammal comprising administering a compound of VIIIa, IX, IXa, A, A1, B and B1.

In addition, the present invention provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, to mammals in need of inhibition of the production of IL-8. A method for inhibiting the production of IL-8 in said mammal comprising administering a compound of VIIIa, IX, IXa, A, A1, B and B1.

In addition, the invention provides an effective amount of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, to a mammal in need of inhibition of the production of TNF. A method of inhibiting the production of TNF in said mammal comprising administering a compound of IX, IXa, A, A1, B and B1.

Accordingly, the present invention provides compounds of formula (I) and formula (I ') having the following structures, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are independently nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

The present invention provides novel compounds of formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1, And pharmaceutically acceptable salt solvates or physiologically functional derivatives thereof. As will be readily appreciated, there is a difference in the degree of unsaturation of the ring system between the compound of formula I and the compound of formula la. Ring substitution on the aryl or heteroaryl moiety of the R ₁ substituent between compounds of Formulas I and Ia and compounds of Formulas II and IIa, III and IIIa, IV and IVa, V and Va, VI and VIa to VIi If possible, there is a difference in the ring position of the nitrogen (s) relative to the pyridyl or pyrimidine residues.

Each R ₁ , R ₂ , R _x , X and R _3, etc. group is identical to one another in the formula itself, e.g. in Formulas I and Ia, with the exception of further G5 / G6 / G7 / G8 groups, which Applicable for all formulas. For the purposes of the present invention, everything applicable to formula (I) is also applicable to formula (Ia) unless otherwise indicated, and to the remaining compounds, such as formulas (II) and (IIa), unless otherwise specified.

For compounds of Formulas (I) and (Ia) in which G ₃ and G ₄ are both carbon and G ₁ and G ₂ are both nitrogen, 2,4,8-trisubstituted-8H-pyrido [2,3- d] pyrimidin-7-one is understood to be regarded as the core ring system.

Compounds of Formulas (I) and (Ia), and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof, are also represented by the following structural formulae.

<Formula I>

<Formula Ia>

Where

G ₁ and G ₂ are independently nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are independently in each case C _{1 - 10} alkyl, halo-substituted C _1-10 alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl carbonyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O), cyano, nitro, aryl, C _{1 -10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, heterocyclyl C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkylNR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N ( R _{10 '} ) C (Z) OR ₇ may be optionally substituted 1 to 4 times), or R ₂ is (CR ₁₀ R ₂₀ ) _q' X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each independently C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _2-10 alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1- 10} alkyl, halogen, -C (O), cyano , nitro, aryl, aryl C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkyl NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR ₇ may be optionally substituted 1 to 4 times),

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are independently in each case C _{1 - 10} alkyl, halo-substituted C _1-10 alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O) , cyano, nitro, aryl, C _{1 -10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, ( CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkyl NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z ) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C ( Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR _e R _e' or (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) OR ₇ may be optionally substituted 1 to 4 times, or R _{2 "} is (CR ₁₀ R ₂₀ ) _t X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} alkyl residue (these residues are all independently represent hydrogen, in each case, halogen, nitro, C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, , C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n C ( Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR ₁₆ R ₂₆ , ( CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR ₁₆ R ₂₆ or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR ₇ optionally substituted one or more times;

R ₄ and R ₁₄ is hydrogen in each case, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ are each independently selected from alkyl moieties, or R ₄ and R ₁₄ is selected from optionally additional oxygen, sulfur or nitrogen, together with the nitrogen to which they are attached To form an unsubstituted or substituted 4- to 7-membered heterocyclic ring containing a heteroatom,

Here, these C _{1 - 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl and heteroaryl C _{1 - 4} alkyl residue and R ₄ and R ₁₄ cyclic moieties are independently at each occurrence halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; SR ₅ ; S (O) R ₅ ; S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) OR ₇ ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) NR _d R _{d ′} , NR _{4 ′} C (O) C _1-10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano; Nitro; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1- 10} alkyl; Unsubstituted or substituted aryl or aryl-C _{1 - 4} alkyl; Unsubstituted or substituted heterocyclic or heterocyclic C _{1 - 4} alkyl; Unsubstituted or substituted heteroaryl or heteroaryl C _{1- 4} is substituted 1 to 4 times, optionally by alkyl, the aryl, heterocyclic and heteroaryl containing moieties are independently halogen, in each case, C _{1 - 4} alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 4} alkoxy, S (O) _m alkyl, amino, mono- or disubstituted with C _{1 - 4} alkyl, amino or one or two times substituted by a CF ₃ Become;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' are cyclized together with the nitrogen to which they are attached, form an oxygen, sulfur or NR To form 5- to 7-membered rings containing additional heteroatoms selected from _{9 '} ;

R _{4 "and} R _14" are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 "and} R _14" are cyclized with the nitrogen to which they are attached, form an oxygen, sulfur or NR To form a 5- to 7-membered heterocyclic ring containing further heteroatoms selected from _{9 '} ;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R ₆ is hydrogen, C ₁ in each case _{- 10} alkyl, C _{3 - 7} cycloalkyl, heterocyclyl, heterocyclyl C _{1- 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl or heteroaryl C _{1 - 10} alkyl is independently selected from (these moieties, excluding hydrogen are optionally substituted, respectively);

R ₇ is in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl moiety (moieties thereof Each may be optionally substituted);

R ₈ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are optionally may be substituted);

R ₉ is hydrogen, C (Z) R _6, optionally substituted C ₁ in each case _{- 10} alkyl, optionally substituted aryl, optionally substituted aryl C _{1 - 4} are independently selected from alkyl;

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl is independently selected from (these moieties, excluding hydrogen are optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₅ and R ₂₅ is hydrogen in each case, C _{1 - 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, aryl, or aryl C _{1 - 4} alkyl, a heterocyclic , a heterocyclic C _{1 - 4} alkyl, heteroaryl or heteroaryl-C _{1 - 4} alkyl moieties each independently selected from (these moieties, excluding hydrogen are optionally may be substituted), or; Or R ₁₅ and R ₂₅ together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or NR ₉ ,

Wherein these moieties except hydrogen are independently at each occurrence halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; C _{1 - 4} alkyl; Halo-substituted C _{1 - 4} alkyl; SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; NR _{4 ′} C (O) C _1-10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano; Nitro; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1- 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl, C _{1 - 4} alkyl, heterocyclic, heterocyclic C _{1- 4} alkyl, heteroaryl or heteroaryl C _{1 - 4} alkyl optionally substituted by one to four times, and the aryl, heterocyclic and heteroaryl halogen-containing residues are also in each case independently, C _{1 - 4} alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 10 alkoxy, S (O) m C 1-} 4 alkyl, amino , mono- or disubstituted with C _{1 - 4} alkylamino, C _{1 - 4} alkyl or may be substituted once or twice by CF _3;

R ₁₆ and R ₂₆ is hydrogen or C ₁ in each case _- or each independently selected from _4-alkyl, or R ₁₆ and R ₂₆ are oxygen, optionally together with the nitrogen to which they are attached, sulfur or a further heteroatom selected from NR _{9 '} To form an unsubstituted or substituted 4- to 7-membered heterocyclic ring containing an atom;

R _{21 'and} R _31' is hydrogen or C ₁ in each case _- are each independently selected from _4-alkyl, or R _{21 'and} R _31' are cyclized together with the nitrogen to which they are attached, form an oxygen, sulfur or NR To form a 5- to 7-membered ring containing additional heteroatoms selected from _{9 '} ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, ₁₀ is an alkyl residue, _- a heterocyclic or heterocyclyl C ₁

Wherein all these residues are independently at each occurrence halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; OR ₈ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR ₁₅ R ₂₅ ; Cyano; Nitro; NR ₁₅ R ₂₅ ; _{-Z '- (CR 10 R 20} ) s -Z'-, C 3 - 7 cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Optionally substituted aryl or arylalkyl, optionally substituted heteroaryl, and heteroaryl C _{1 - 10} alkyl, and optionally substituted heterocyclic group, and a heterocyclic C _{1 -} by ₁₀ alkyl and may be optionally substituted one to four times, the aryl, heteroaryl and heterocyclic containing moieties may also independently halogen, hydroxy, hydroxy in each case substituted alkyl, C _{1 - 10} alkoxy, S (O) _m C _1-4 alkyl, amino, It is mono-or di-substituted C _{1 - 4} alkylamino, C _{1 - 4} alkyl or may be substituted once or twice by CF _3;

R _d and R _{d 'is} hydrogen, C ₁ in each case _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C _{1 - 4} are each independently selected from alkyl, or R _d and R _{d '} Together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or NR _9' ,

Here, C _{1 -} to ₄ alkyl, R _d and R _{d 'residues} and R _d and R _d', if each of the annular rings is independently _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ halogen, halo-substituted C _{1 --substituted} C _{1 - 4} alkyl, hydroxy, _hydroxy-4 alkyl, C _{1 - 4} alkoxy, halo-substituted C _{1 - 4} alkoxy, S (O) _m R _{f, C (O) R j, C} (O) OR j, C (O) NR 4 'R 14', NR 4 'C (O) C 14 _{alkyl, S (O) 2 NR 4} ' R 14 'C _{14 alkyl, NR 4 'R 14' S} (O) 2 C 1-4 substituted one to four times by alkyl, or NR _{4 'R 14';}

R _e and R _{e 'is} hydrogen, C ₁ in each case _{- 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl or heteroaryl C _{1 - 4} are each independently selected from alkyl moieties; Or R _e and R _{e ′} together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen,

Wherein these moieties except hydrogen are each independently halogen in each case; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; Amino, mono- or disubstituted with C _{1 - 4} alkyl amino, S (O) _m R _f; C (O) R _j ; C (O) OR _j ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) OR ₇ ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) NR _d R _{d ′} ; C (O) NR _{4 '} R _14' ; _{NR 4 'C (O) C} 1- 10 alkyl; NR _{4 '} C (O) aryl; Cyano; Nitro; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl, C _{1 - 4} alkyl, heterocyclic, heterocyclic C _{1 - 4} alkyl, heteroaryl or heteroaryl C _{1 -} by _4-alkyl may be optionally substituted one to four times each, and the aryl, heterocyclic and heteroaryl containing moieties independently selected from halogen, C ₁ in each case, _{- 4} alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 10} alkoxy, S (O) _m alkyl, amino, mono-substituted or disubstituted with C _{1 - 4} alkylamino, C _{1 - 4} alkyl may be optionally substituted by CF ₃ or 1 or 2 times;

R _f is C ₁ in each case _{- 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl C _1-10 alkyl, heterocyclic or heterocyclic C _{1 - 10} alkyl moiety (moieties thereof Optionally substituted);

R _j is hydrogen, C ₁ in each case _{- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl C _{1- 4} alkyl, heterocyclic or heterocyclic C _{1 - 4} alkyl residue (hydrogen These residues except may be optionally substituted);

g is 0 or an integer having a value of 1, 2, 3 or 4;

n is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

s is independently selected from each integer having a value of 1, 2 or 3 in each case;

t is an integer having a value of 2 to 6;

Z in each occurrence is independently selected from oxygen or sulfur;

Z 'is independently selected in each case from oxygen, nitrogen or sulfur.

Suitably, for compounds of Formulas (I) and (Ia), and compounds of the remaining formulas described herein, R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 ′} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b .

In one embodiment of the invention, R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b to be. In other embodiments of the invention, R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b .

Suitably, R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', ( CR ₁₀ R ₂₀ ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ .

In one embodiment, R _{1 'is} halogen, C ₁ in each case _- is independently selected from substituted C _{1-4 alkyl-4-alkyl} or halo. In other embodiments, R _{1 ′} in each occurrence is independently selected from fluorine, chlorine, methyl or CF ₃ .

Suitably g is 0 or an integer having a value of 1, 2, 3 or 4. In one embodiment of the invention, g is 0, 1 or 2.

In the case of compounds of formulas (I) and (Ia), if R _{1 ′} is substituted at the ortho position on the phenyl ring and the second R _{1 ′} residue is also substituted on the ring, the second substitution is preferably not at another ortho position. Suitably, the phenyl ring is substituted at the 2-position and, if a second substituent is present, is substituted at the 3-position with the R ₁ residue at the 5-position. Alternatively, the R _{1 ′} residue may be at another ortho 2-position and the R ₁ residue may be at 3-position, which will change the ring position number.

Suitably, R _d and R _{d 'is} hydrogen in each case, C _{1 - 4} alkyl, C _{3 - 5} cycloalkyl, C _{3 - 5} cycloalkyl, C _{1- 4} are each independently selected from alkyl, or R _d and R _{d '} together with the nitrogen to which they are attached form an optionally substituted 5- or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR _9' , wherein C _{1 -4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C _{1 - 4} alkyl, R _d and R _{d 'and} R _d moiety, and R _d' annular ring are halogen, in each case independently; Halo-substituted C _{1 - 4} alkyl; Hydroxy; A hydroxy-substituted C _{1 - 4} alkyl; C _{1 - 4} alkoxy; C _{1 - 4} alkyl; Halo-substituted C _{1 - 4} alkoxy; S (O) _m R _f ; C (O) R _j ; C (O) OR _j ; _{C (O) NR 4 'R} 14', NR 4 'C (O) C 14 alkyl; _{S (O) 2 NR 4 '} R 14' C 14 alkyl; _{NR 4 'R 14' S (} O) 2 C 14 alkyl; Or optionally 1 to 4 times by NR _{4 ′} R _{14 ′} .

Suitably, R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl.

Suitably Z is independently selected in each case from oxygen or sulfur.

Suitably, v is 0 or an integer having a value of 1 to 2.

Suitably v 'is 0 or an integer having a value of 1 or 2.

Suitably, R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl.

Suitably, R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl.

Suitably, R ₁₂ is hydrogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heterocyclyl, or heterocyclyl C _{1 - 4} alkyl are independently selected from (these moieties, excluding hydrogen are optionally may be substituted).

Suitably, R ₁₃ is hydrogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heterocyclyl, or heterocyclyl C _{1 - 4} are independently selected from alkyl moieties, these moieties, excluding hydrogen, where is halogen, in each case independently a halo-substituted C _{1 - 4} alkyl; C _{1 -4} alkyl; Hydroxy; A hydroxy-substituted C _{1 - 4} alkyl; C _{1 - 4} alkoxy; Halo-substituted C _{1 - 4} alkoxy; S (O) _m C _{1- 4} alkyl; -C (O), C (O ) C 1- 4 alkyl; Or optionally 1 to 4 times by NR _{21 ′} R _{31 ′} .

Suitably, R _{21 'and} R _31' is hydrogen or C ₁ in each case _- are each independently selected from _4-alkyl, or R _{21 'and} R _31' are cyclized together with the nitrogen to which they are attached, form O To form an optionally substituted 5- to 7-membered heterocyclic ring containing additional heteroatoms selected from / N / S.

Suitably R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10-alkyl,} heterocyclic or heterocyclyl C _{1- 10} alkyl residue is (these moieties, excluding hydrogen are all optionally substituted).

R _b moieties other than hydrogen are independently at each occurrence halogen, such as fluorine, chlorine, bromine or iodine; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy, such as methoxy or ethoxy; Halo-substituted C _{1 - 10} alkoxy; OR ₈ , such as methoxy, ethoxy or phenoxy; SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ , such as methylthio, methylsulfinyl or methylsulfonyl; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 "} R _{14 "} ; Cyano; Nitro; NR ₁₅ R ₂₅ ; -Z '-(CR ₁₀ R ₂₀ ) _s -Z'-; C _{1 -10} alkyl; C _{3 - 7} cycloalkyl or C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl group such as cyclopropyl, cyclopropyl-methyl or cyclopropyl-ethyl, and the like; Halo-substituted C _{1 - 10} alkyl, such _{CF 2 CF 2 H, CH 2} CF 3 or CF _3; Optionally substituted aryl such as phenyl; Or an optionally substituted aryl C _{1 - 10} alkyl, such as benzyl or phenethyl; An optionally substituted heterocyclic or heterocyclic C _{1 -10} alkyl; Or optionally substituted heteroaryl or heteroaryl C _{1-substituted-by} a _10-alkyl, optionally one or more times, preferably can be optionally substituted one to four times, and the aryl, heteroaryl and heterocyclic containing moieties may also each independently If halogen, hydroxy, hydroxy-on-a ₄ alkyl or CF _{3 -} substituted alkyl, C _{1 - 10} alkoxy, S (O) _m alkyl, amino, mono- or disubstituted with C _{1 - 4} alkylamino, C ₁ It may be substituted once or twice.

The -Z '-(CR ₁₀ R ₂₀ ) _s -Z' residue forms a cyclic ring, such as a dioxalan ring.

Suitably Z 'in each case is independently selected from oxygen or sulfur.

Suitably, s is independently selected from each integer having a value of 1, 2 or 3 in each case.

Suitably, R ₅ is hydrogen in each case, C ₁₄ alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, or are independently selected from NR _{4 'R 14'} (the SNR moieties SR _{5 4 ′} R _{14 ′} , except when S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH.

Suitably, R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' are cyclized together with the nitrogen to which they are attached, form an oxygen , Optionally substituted 5- to 7-membered rings containing additional heteroatoms selected from sulfur or NR _{9 ′} . Suitably, when R _{4 ′} and R _{14 ′} are cyclized to form an optionally substituted ring, such rings include pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine (including oxidation of sulfur) There is, but is not limited to these.

Suitably, R _{4 "and} R _14" is hydrogen or C ₁ in each case _- are each independently selected from the _10-alkyl, or R _{4 "and} R _14" are cyclized with the nitrogen to which they are attached, form an oxygen , Optionally substituted 5- to 7-membered rings containing additional heteroatoms selected from sulfur or NR _{9 ′} . Suitably, when R _{4 ″} and R _{14 ″} are cyclized to form an optionally substituted ring, such rings include pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine (including oxidation of sulfur) There is, but is not limited to these.

Suitably, R _f is hydrogen in each case, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclic C _{1 - 10} Independently from alkyl moieties (other moieties except hydrogen may be optionally substituted).

Suitably, R _j is in each case C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl C _{1- 10} alkyl, heterocyclic or heterocyclic C _{1 - 10} alkyl moiety (These residues may each be optionally substituted).

Suitably, R _b is optionally substituted C _{1 - 10} alkyl, if the residues are methyl, ethyl, n- propyl, isopropyl, t- butyl, n- butyl, isobutyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, heptyl, 2-methylpropyl; Halo-substituted alkyls such as 2,2,2-trifluoroethyl, trifluoromethyl, 2-fluoroethyl; Cyano-substituted alkyls such as cyanomethyl, cyanoethyl; Alkoxy, thio or hydroxy-substituted alkyls such as, but not limited to, 2-methoxy-ethyl, 2-hydroxy propyl or serinol or ethylthioethyl.

In alternative embodiments of, R _b is optionally substituted C _{1 - 10} when the alkyl residues are methyl, ethyl, n- propyl, isopropyl, t- butyl, n- butyl or 2,2-dimethylpropyl, or 2 -A hydroxy propyl group.

Suitably, when R _b is optionally substituted heteroaryl or heteroarylalkyl, the heteroaryl containing moiety is furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, already Dazolyl, pyrazolyl, oxdiazolyl, oxthiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, uracil, indolyl, isoindoleyl , Indazolyl, indolinyl, azaindoleyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyrididi Nil, cinnaolinyl, purinyl and phthalazinyl.

In one embodiment, when R _b is optionally substituted heteroaryl, it is 1,3-thiazol-2-yl or 5-methyl-1,3-thiazol-2-yl, isoquinolinyl, thiophene For example 3-thiophene, indol-5-yl, pyridinyl, for example pyridin-3-yl or pyridin-4-yl, indazolyl, benzothiazolyl, 2-methyl-1,3-benzothia Sol-5-yl, 1H-imidazol-4-yl or 1H-imidazol-4-ylethyl. In addition, the heteroaryl ring is an optionally substituted thiazolyl, pyridyl or thiophene ring. Preferably, R _b is optionally substituted 1,3-thiazol-2-yl.

Suitably, when R _b is optionally substituted heterocyclic or heterocyclicalkyl, the heterocyclic containing moiety is tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (oxidized form of sulfur moiety) Azepine, diazepine, aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5 -Yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino (including oxidized forms of sulfur residues) Including but not limited to. In one embodiment, the heterocyclic, heterocyclicalkyl group is pyrazol-3-yl, 4-morpholino, unsubstituted and substituted 2-furanyl, 2-furanylmethyl, 2-thienyl, 2- Thienylmethyl, tetrahydro-2H-pyran-4yl, tetrahydro-2H-pyran-4yl methyl, tetrahydro-2-furanyl or tetrahydro-2-furanylmethyl.

Suitably, when R _b is an optionally substituted aryl or arylalkyl moiety, the aryl containing moiety is independently unsubstituted in each case or halogen, alkyl, cyano, OR ₈ , SR ₅ , S (O) _{2 R 5, C (O)} R j, C (O) oR j, -Z '- (CR 10 R 20) s -Z', halo-substituted C _{1 - 10} alkyl or optionally substituted aryl by 1 It is substituted more than once.

In one embodiment, R _b is phenyl, naphthylene, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3 , 4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 6 -Methylphenyl, 2-methylphenyl, 3-aminophenyl, 3,4-dimethylphenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl, 4-ethoxyphenyl, 4-methoxyphenyl, 3- Cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4-acetylphenyl, 4-dimethylaminophenyl, benzyl, phenethyl, phenylpropyl, 2,3-difluoro-benzyl, 3,5-difluoro Rho-benzyl, biphenyl, 4'-fluorobiphenyl, 4-sulfonamido-2-methylphenyl, 3-phenyloxyphenyl, 4-phenyloxyphenyl, 4- (1-piperidinylsulfonyl) -phenyl or 3 -(Aminocarbonyl) phenyl.

In other embodiments, R _b is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5- Difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-ethoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4-acetylphenyl, 4-dimethylaminophenyl, biphenyl, 4'-fluorobiphenyl, 4-sulfonamido-2-methylphenyl, 3-phenyloxyphenyl, benzyl or phenethyl. In addition, R _b is 4-fluorophenyl.

Suitably, when R _b is an optionally substituted cycloalkyl or cycloalkylalkyl moiety, the moiety is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or cyclopentylmethyl. In other embodiments, R _b is a cyclopropyl or cyclopropylmethyl group.

In other embodiments, R _b is C _{1 - 10} is alkyl, heteroaryl or aryl (all optionally substituted).

In other embodiments, R _b is hydrogen or optionally substituted alkyl.

In one embodiment of the invention, R _b is alkyl such as propyl or isopropyl; Heteroaryl, such as thiazolyl; Aryl such as phenyl or 4-F phenyl; Arylalkyl; Or cycloalkylalkyl moieties, all optionally substituted. In other embodiments, R _b is alkyl, heteroaryl or aryl, all optionally substituted.

In other embodiments, R _b is C _{1 - 10} is alkyl, heteroaryl or aryl (all optionally substituted).

Suitably, m is independently selected from each integer having a value of 0, or 1 or 2 in each case.

Where appropriate, each integer variable, for example n, n ', m, q', s, t or v ', etc., is independently selected in each case.

Suitably, R ₈ is hydrogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 -7} cycloalkenyl C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4-alkyl,} heterocyclyl or heterocyclyl C _{1 - 4} are independently selected from alkyl residue, wherein these residues is a halogen other than hydrogen; Halo-substituted C _{1 - 4} alkyl; C _{1 - 4} alkyl; C _{3 - 5} cycloalkyl; C _{3 -5} cycloalkyl C _{1 -4} alkyl; Halo-substituted C _{1 - 4} alkyl; Hydroxy; A hydroxy-substituted C _{1 - 4} alkyl; C _{1 - 4} alkoxy; Halo-substituted C _{1 - 4} alkoxy; S (O) _m C _1-4 alkyl; -C (O), C (O ) C 1- 4 alkyl; NR _{21 '} R _31' ; Or aryl, or may be by an aryl group optionally substituted 1 to 4 times, and the aryl-containing moieties include, but are also independently selected from halogen, in each case, hydroxy, hydroxy-substituted alkyl, C _{1 - 4} alkoxy, S (O ) _m C _{1- 4} alkyl, amino, mono- and di C _{1 - 4} alkyl which may be substituted or 1 or 2 times by CF _{3 - 4} alkylamino, C _1.

Suitably, R ₁₅ and R ₂₅ is hydrogen, C ₁ in each case _{- 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl or heteroaryl-C _{1 - 4} alkyl moieties each independently selected from (these moieties, excluding hydrogen are optionally may be substituted), or; Or R ₁₅ and R ₂₅ together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR ₉ , wherein these residues Is independently at each occurrence a halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; C _{1 -4} alkyl; SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; _{NR 4 'C (O) C} 1- 10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano; Nitro; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl, C _{1 - 4} alkyl, heterocyclic and heterocyclic C _{1 - 4} alkyl, heteroaryl or heteroaryl C _{1 -} by _4-alkyl is optionally substituted one to four times, and the aryl, heterocyclic and heteroaryl halogen-containing residues are also in each case independently, C _1-4 alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 10} alkoxy, S (O) _m alkyl, amino, mono- or disubstituted C _{1 - 4} alkylamino, C _{1 - 4} may be substituted once or twice by alkyl or CF _3.

Suitably, R ₄ and R ₁₄ is hydrogen in each case, optionally substituted C _{1 - 10} alkyl, optionally substituted C _{3 - 7} cycloalkyl, optionally substituted C _{3 - 7} cycloalkyl, C ₁₄ alkyl, optionally substituted aryl or optionally substituted aryl C _{1 - 4} alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1- 4} alkyl, cyclic optionally substituted heteroaryl or optionally substituted hetero cyclic C _{1 - 4} alkyl Each independently selected from R ₄ and R ₁₄ together with the nitrogen to which they are attached optionally form an optionally substituted 4- to 7-membered heterocyclic ring containing additional heteroatoms selected from oxygen, sulfur or nitrogen; Form.

Except for hydrogen C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 4} alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heterocyclic click, or heterocyclic C ₁₄ R ₄ and R ₁₄ residue and R ₄ and R ₁₄ are both annular rings in each case independently halogen, such as fluorine, chlorine, bromine or iodine in the alkyl moiety; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy, such as methoxy or ethoxy; C _{1 - 10} alkyl, halo-substituted C _{1 -10} alkoxy; SR ₅ ; S (O) R ₅ ; S (O) ₂ R ₅ such as methylthio, methylsulfinyl or methylsulfonyl; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) OR ₇ ; _{(CR 10 R 20) n N} (R 10 ') C (Z) NR d R d', NR 4 'C (O) C 1- 10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano; Nitro; C _{1 - 10} alkyl, such as methyl, ethyl, n- propyl, t- butyl and the like; C _{3 - 7} cycloalkyl and C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, such as cyclopropyl, cyclopropyl-methyl or cyclopropyl-ethyl, and the like; Halo-substituted C _{1 - 10} alkyl, such _{CF 2 CF 2 H, CH 2} CF 3 or CF _3; Optionally one or more times with a substituted aryl-substituted C _{1 - 10} alkyl; Optionally substituted aryl such as phenyl; Or optionally substituted aryl C _{1 - 4} alkyl, such as benzyl or phenethyl; Unsubstituted or substituted heteroaryl or heteroaryl C _{1 - 4} alkyl, unsubstituted or substituted heterocyclic or heterocyclic C _{1 -} by _4-alkyl optionally once or more, and preferably is substituted one to four times, the aryl, heteroaryl and heterocyclic containing moiety also halogen, in each case independently, C _{1 - 4} alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 4} alkoxy, S (O) the _m-alkyl, amino, mono- or disubstituted C _{1 - 4} alkyl or amino may be optionally substituted by CF ₃ or 1 or 2 times.

Suitably, when R ₄ and R ₁₄ are cyclized with nitrogen to form an optionally substituted ring as described above, such rings include pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine (Including oxidation of sulfur), but not limited to these.

Suitably, R ₆ is hydrogen in each case, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, heterocyclyl, heterocyclyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl or heteroaryl C _{1 - 10} are independently selected from alkyl moieties, these moieties, excluding hydrogen, where halogen is in each case independently; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _1-10 alkoxy; S (O) _m alkyl; C (O); NR _{4 '} R _14' ; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1- 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Unsubstituted aryl or aryl C _{1 - 4} alkyl, unsubstituted or substituted heteroaryl or heteroaryl-C _{1 - 4} alkyl, or unsubstituted or substituted heterocyclic or heterocyclic C _{1 -} by _4-alkyl, optionally one or more times, suitably one or two times may be substituted, the aryl, heterocyclic or heteroaryl containing moieties independently selected from halogen, hydroxyl, in each case, a hydroxy-substituted alkyl, C _{1 - 10} alkoxy , S (O) _m alkyl, amino, mono- or disubstituted with C _{1 - 4} may be alkyl or CF ₃ 1 once or twice _{substituted-4} alkylamino, C _1.

Suitably, R ₉ is hydrogen, C (Z) R _6, optionally substituted C ₁ in each case _- are independently selected from _{4-alkyl-10-alkyl,} optionally substituted aryl or optionally substituted aryl C _1. These alkyl, aryl and arylalkyl moieties are independently at each occurrence halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; S (O) _m alkyl; -C (O); NR _{4 '} R _14' ; C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl or C _{1 -} by _4-alkyl optionally can be substituted once or twice, and the aryl-containing moieties include, but are also independently selected from halogen, hydroxy, hydroxy in each case substituted alkyl, C _{1 - 10} alkoxy, ₄ may be substituted alkyl or CF ₃ in once or twice by _{- S (O) m C 1-} 4 alkyl, amino, mono- or disubstituted with C _{1 - 4} alkylamino, C _1.

Suitably, R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1- 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 -10} alkyl residue, wherein these residues are independently selected from hydrogen, halogen, nitro, in each case, C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 -7} cycloalkyl C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) NR ₁₆ R ₂₆ , or (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) OR ₇ optionally one or more times , Preferably 1 to 4 times.

In one embodiment, R ₃ moieties independently selected from halogen, nitro, C ₁ in each case, _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 6} cycloalkyl, C _3-6 cycloalkyl C _1-4 alkyl, C _{5 - 6} cycloalkenyl, C _{5 - 6} cycloalkenyl C _{1 - 4 alkyl, (CR 10 R 20) n} OR 6, ( CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n NHS (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z ) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ or (CR ₁₀ R ₂₀ ) _n C (Z) NR Optionally substituted 1 to 4 times by ₁₆ R ₂₆ .

In one embodiment, R ₃ moieties independently selected from halogen, C ₁ in each case, _{- 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n NR 16 R 26 or halo-substituted C ₁ by any of the R ₃ substituents independently selected from alkyl, optionally ₁₀ or more times, suitably substituted with one to four times independently.

In another embodiment, any of the substituents are halogen, C ₁ in each case _{- 10} alkyl, hydroxy, C _{1 - 10} alkoxy, cyano, nitro, amino or halo-independently selected from the _{10-alkyl-substituted} C ₁ do. In another embodiment, R ₃ substituent is halogen such as fluorine, chlorine, bromine or iodine, or C _{1 - 10} is independently selected from alkyl such as methyl.

In one embodiment, R ₃ moieties include optionally substituted C _{1 -1O} alkyl, optionally substituted C _{3 - 7} are selected from alkyl, cycloalkyl or optionally substituted _aryl-7 cycloalkyl, optionally substituted C _3. In another embodiment, R ₃ moieties include optionally substituted C _{1 - 10} alkyl, or is selected from optionally substituted aryl. In other embodiments, R ₃ is optionally substituted phenyl. In addition to the above embodiments, R ₃ is independently at each occurrence a phenyl ring substituted one or more times with fluorine, chlorine, hydroxy, methoxy, amino, methyl or trifluoromethyl. Preferably, R ₃ is 2,6-difluorophenyl.

Suitably, in one embodiment when R ₃ is an aryl moiety, it is a phenyl ring. Phenyl ring is independently halogen, C ₁ in each _case is by the _4-alkyl, optionally one or more times, suitably 1 to 4 times a _{substituted-4-alkyl} or halo-substituted C _1. The phenyl ring may suitably be substituted at the 2, 4 or 6-position or di-substituted at the 2,4- or 2,6-position (eg, 2-fluoro, 4-fluoro, 2,4-di Fluoro, 2,6-difluoro or 2-methyl-4-fluoro) or may be trisubstituted (eg, 2,4,6-trifluoro) at the 2,4,6-position have.

Suitably, R ₇ is C ₁ for each occurrence _- from _{6 alkyl-6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1 - 6} alkyl, heteroaryl or heteroaryl C ₁ Independently selected, wherein these moieties are each independently of each other a halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; S (O) _m alkyl; C (O); NR _{4 '} R _14' ; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl or C _{1 - 4} may be optionally substituted one or two times by alkyl moiety, the aryl containing moiety is also halogen, hydroxy, hydroxy-substituted alkyl, C _{1 - 10} alkoxy, S (O) _m alkyl, amino, mono- or disubstituted with C _{1 - 4} alkylamino, C _{1 - 4} may be substituted once or twice by alkyl or CF _3.

Suitably, R ₁₆ and R ₂₆ is hydrogen or C ₁ in each case _- are each independently selected from _4-alkyl; Or R ₁₆ and R ₂₆ together with the nitrogen to which they are attached form an unsubstituted or substituted 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR _{9 ′} .

Suitably n is 0 or an integer having a value of 1 to 10.

Suitably, X is R ₂ , OR _{2 ′} , S (O) _m R _{2 ′} , (CH ₂ ) _{n ′} N (R _{10 ′} ) S (O) _m R _{2 ′} ; (CH ₂ ) _{n '} N (R _10' ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 ′} ) R _h NH—C (═N—CN) NR _q R _{q ′} .

In one embodiment of the invention X is N (R _{10 ′} ) R _h NH—C (═N—CN) NR _q R _{q ′} .

Suitably, X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ . In one embodiment of the invention, X ₁ is N (R ₁₁ ) or O.

Suitably, R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH ₂ -,- CH ₂ -C (O) O-CH ₂ -CH ₂ -or -CH ₂ -CH ₂ -OC (O) CH _2- .

Suitably, R _q, and R _{q 'is} hydrogen, C ₁ in each case _{- 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1- 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl moiety (except hydrogen All of these moieties are optionally substituted) or R _q and R _{q ′} are optionally substituted 5-membered which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur together with the nitrogen to which they are attached; To 7-membered heterocyclic ring.

Suitably, R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl.

Suitably, R ₂ is hydrogen, optionally substituted C _{1 - 10} alkyl, optionally substituted C _{3 - 7} cycloalkyl, optionally substituted C _{3 - 7} cycloalkyl alkyl, optionally substituted aryl, optionally substituted aryl C _{1 -10} alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 - 10} alkyl, optionally substituted heterocyclic, optionally substituted heterocyclyl C _{1 - 10} independently selected from alkyl moieties; Or R ₂ is (CR ₁₀ R ₂₀ ) _{q '} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _q' C (A ₁ ) (A ₂ ) (A ₃ ) residues.

Suitably q 'is 0 or an integer having a value of 1-6.

R ₂ moieties, excluding hydrogen are independently in each case C _{1 - 10} alkyl, halo-substituted C _1-10 alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O), cyano, nitro, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkylNR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) _n C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR by ₇ optionally one or more times, preferably 1 to 4 times a value It can be.

Suitably, R _e and R _{e 'is} hydrogen, C ₁ in each case _{- 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl , heteroaryl or heteroaryl C _{1 - 4} alkyl moieties each independently selected from (these moieties optionally may be substituted), or; Or R _e and R _{e ′} together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR ₉ , wherein hydrogen Except for these residues (including cyclic rings) each independently represents in each case a halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 -10} alkoxy; C _1-10 alkyl; Halo-substituted C _{1 - 4} alkyl; S (O) _m R _f ; C (O) R _j ; C (O) OR _j ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) OR ₇ ; (CR ₁₀ R ₂₀ ) _n N (R _{10 ′} ) C (Z) NR _d R _{d ′} ; C (O) NR _{4 '} R _14' ; _{NR 4 'C (O) C} 1- 10 alkyl; NR _{4 '} C (O) aryl; Cyano; Nitro; NR _{4 '} R _14' ; C _{1 - 10} alkyl; C _{3 - 7} cycloalkyl; C _{3 - 7} cycloalkyl, C _{1 -10} alkyl; Halo-substituted C _{1 - 10} alkyl; Aryl, C _{1 - 4} alkyl, heterocyclic, heterocyclic C _{1 -4} alkyl, heteroaryl or heteroaryl C _{1 - 4} alkyl may be optionally substituted by one to four times, and the aryl, heterocyclic or heteroaryl aryl containing moiety is a halogen, in each case independently, C _{1 - 4} alkyl, hydroxy, hydroxy-substituted C _{1 - 4} alkyl, C _{1 - 10} alkoxy, S (O) _m alkyl, amino, mono- or disubstituted C _1-4 alkylamino, C _{1 - 4} alkyl, or optionally substituted once or twice by CF _3.

Suitably, R _{f 'is} hydrogen in each case, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclic C _{1 -} Independently selected from ₁₀ alkyl moieties (other moieties except hydrogen may be optionally substituted).

When X is R ₂ and R ₂ is optionally substituted heterocyclic or heterocyclic alkyl, the heterocyclic containing moiety is suitably tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (sulfur Aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5- Selected from one, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino (including oxidized forms of sulfur residues) do.

In one embodiment, R ₂ is an optionally substituted piperidinyl or piperazinyl ring.

In other embodiments, when R ₂ is an optionally substituted heterocyclic or heterocyclic alkyl ring, the ring is independently optionally substituted heterocyclic, heterocyclic alkyl, aryl, arylalkyl, alkyl, (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR ₇ is substituted one or more times. The second heterocyclic ring is suitably optionally substituted tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized forms of sulfur residues), aziridinyl, pyrrolinyl, pyrrolidinyl , 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, Pyrazolidinyl, piperidinyl, piperazinyl, diazepine, morpholino or thiomorpholino, including oxidized forms of sulfur residues. Suitably, the second heterocyclic ring is selected from morpholino, piperidine or pyrrolidinyl.

In one embodiment, R ₂ is 4-amino-1-piperidinyl, 1,1-dimethylethyl) oxy] -carbonyl} amino) -1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-butyl-1-piperazinyl, 4- (methylamino) -1-piperidinyl, 1,1-dimethylethyl- 4-piperidinyl} methylcarbamate, 4-phenyl-1-piperazinyl, 1,4'-bipiperidin-1'-yl, 4- (1-pyrrolidinyl) -1-piperidinyl , 4-methyl-1,4'-bipiperidin-1'-yl, 4- (4-morpholinyl) -1-piperidinyl, 4- (diphenylmethyl) -1-piperazinyl or 4 -Methylhexahydro-1H-1,4-diazepin-1-yl.

Suitably, R _{2 'is} hydrogen, C ₁ in each case _{- 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl C _{1 -} is independently selected from ₁₀ alkyl residue, in which case these moieties are each independently other than hydrogen to the C _{1 - - 10} alkyl, heterocyclic or heterocyclyl C _{1 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 -7} cycloalkyl alkenyl, C _{1- 10} alkyl, halogen, -C (O), cyano, nitro, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, heterocyclyl C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n SH, (CR 10 R 20) n S (O) m R 7, (CR 10 R 20) n n (R 10 ' ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkylNR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R Optionally substituted 1 to 4 times with _{10 '} ) C (Z) OR ₇ .

In one embodiment, when X is (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ), either R _{2 ′} or R _{2 ″} is hydrogen or methyl.

In one embodiment, R _{2 'is} an optionally substituted heterocyclic or heterocyclyl C _{1 -} For ₁₀ alkyl, the heterocyclic containing moiety is independently selected from C _{1 - 10} alkyl, aryl, heterocyclic, (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR ₇ or (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ is substituted one or more times . More specifically, methyl, ethyl, NHC (O) O-CCH ₃ , N (CH ₃ ) C (O) O-CCH ₃ , amino, methylamino, dimethylamino, phenyl, piperidine, pyrrolidine, 1-ethylpropyl, 4-methyl-1,4'-bipiperidin-1'-yl, 1,4'-bipiperidin-1'-yl, morpholino.

In one _embodiment, when the _{(R 2 "), R 2} X is _{(CH 2) n N (R} 2) ' is an optionally substituted C _{1 - 10} alkyl, cycloalkyl, heterocyclic, heterocyclyl C _{1 -} is a _10-alkyl, heteroaryl-alkyl suitably, when R _{2 'optionally} is substituted cycloalkyl, it is a cyclohexyl ring in one embodiment, the cyclohexyl ring is _{(CR 10 R 20) n NR} e Optionally substituted one or more times with R _{e '} .

Suitably, R _{2 'is} an optionally substituted heterocyclic or heterocyclyl C _{1 -} when the _10-alkyl, ring-tetrahydro pyrrole, tetrahydropyran, tetrahydrofuran, tetrahydro-thiophene (the oxidation of the sulfur residues Forms), aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5-yl, imida Zolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine, hexahydro-1H-azepine, morpholino or thiomorpholino (of sulfur residues) In oxidized form). Preferably, the ring is a piperidine, piperazine, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, morpholino, hexahydro-1H-azepine ring. In one embodiment, the rings are independently selected from C _{1 -} C (Z) _10-alkyl, aryl, _{arylalkyl, (CR 10 R 20) n} NR e R e ' or _{(CR 10 R 20) n N} (R 10') It is substituted 1 or more times suitably by OR <_7> suitably.

In one embodiment, (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ) is 1- (phenylmethyl) -4-piperidinamine, 2- [4- (phenylmethyl) -1-pipera Genyl] ethylamine, 2- (1-piperidinyl) ethylamine, 2- (1-methyl-2-pyrrolidinyl) ethylamine, 1-[(phenylmethyl) -3-pyrrolidinyl] amine, 3 -[(1-pyrrolidinyl) propyl] amine, 3-[(hexahydro-1H-azin-1-yl) propyl] amine, (1-methyl-4-piperidinyl) amine, 3-[( 4-morpholinyl) propyl] amine, 3-[(2-oxo-1-pyrrolidinyl) propyl] amine, 2-[(4-morpholinyl) ethyl] amine, 2-[(1-pyrroli Diyl) ethyl] amine or [(1-ethyl-2-pyrrolidinyl) methyl] amino.

In one embodiment, X is _{(CH 2) n N (R} 2 ') (R 2 ") , and, R _2' is an optionally substituted C _{1 -} when the _10-alkyl, alkyl is a (CR ₁₀ R ₂₀₎ independently _n NR _e R _{e 'or (CR 10 R 20) n NR} e R e' C 1 - 4 alkyl, NR _e R _{e '.} is substituted one or more times with a in one embodiment, R _e and R _e' are independently in the optionally substituted C _{1 -4} alkyl, such as methyl, ethyl, isopropyl, n- butyl or t- butyl. _{preferably, (CH 2) n n (} R 2 ') (R 2 ") is 3 (Dimethylamino) propyl (methyl) amine, 3- (diethylamino) propylamine, propylamine, (2,2-dimethylpropyl) amine, (2-hydroxypropyl) amino, 2- (dimethylamino) ethylamine , 2- (dimethylamino) ethyl (methyl) amine, 3- (dimethylamino) propylamine, 2- (dimethylamino) ethyl (methyl) amine, 3- (diethylamino) propylamine, 2- (methylamino) Ethylamine, [(1-methylethyl) amino] ethylamine, 3- (diethylamino) propylamine, 3- (dibutylamino) propyl Min, 3-[(1-methylethyl) amino] propylamine, 3- (1,1-dimethylethyl) aminopropylamine, 3- (dimethylamino) -2,2-dimethylpropylamine, 4- (diethyl Amino) -1-methylbutylamine or 3-[[3- (dimethylamino) propyl]-(methyl) amino] propyl (methyl) amine.

Suitably, R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, , a heterocyclic or heterocyclyl C _{1- 10} alkyl moieties (these moieties, excluding hydrogen are independently in each case C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, - C (O), cyano, nitro, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, heterocyclyl C _1-10 alkyl, (CR ₁₀ R _{20) n} OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR _{10 R 20) n NR e R} e ', ((CR 10 R 20) n NR e R e' C 1 - 4 alkyl, _{NR e R e ', (CR} 10 R 20) n CN, (CR 10 R 20) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR _{7 which} may be optionally substituted 1 to 4 times; Or R _{2 ″} is (CR ₁₀ R ₂₀ ) _t X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) residues.

Suitably t is an integer having a value of 2-6.

Suitably q is 0 or an integer having a value from 1 to 10.

Suitably, A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl, or aryl C _{1 -} from ₁₀ alkyl .

Suitably, A ₂ is an optionally substituted C _{1 -} is a _10-alkyl-10 alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl C _1.

Suitably, A ₃ is hydrogen or an optionally substituted C _{1 - 10} is alkyl.

A _1, A ₂ and A ₃ C _{1 - 10} alkyl moiety is in each case independently halogen, such as chlorine, fluorine, bromine, or iodine; Halo-substituted C _{1 - 10} alkyl, such as CF ₃ or CHF ₂ CF _3; C _{2 -10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n SH, (CR 10 R 20) n S (O) m R 7, (CR 10 R 20) n n (R 10 ' ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR ₄ R ₁₄ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₄ R ₁₄ , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR ₄ R ₁₄ ; (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR ₄ R ₁₄ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₄ R ₁₄ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR ₄ R ₁₄ or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) OR ₇ may be optionally substituted one or more times, preferably 1 to 4 times.

In another embodiment of the invention, X is R ₂ and R ₂ is (CR ₁₀ R ₂₀ ) _{q '} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ). In a further embodiment, q 'is zero.

In other embodiments when R ₂ is (CR ₁₀ R ₂₀ ) _{q '} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) residues, q' is 0 and X ₁ is Nitrogen, q is 0 or 1, A ₁ is optionally substituted heterocyclic or heterocyclic alkyl, and A ₂ is optionally substituted aryl. More specifically, R ₂ is 2-phenyl-2- (1-pyrrolidinyl) ethyl] amino or 1-phenyl-2- (1-pyrrolidinyl) ethyl] amino.

In one embodiment of the invention, at least one of A ₁ , A ₂ and A ₃ residues is substituted with (CR ₁₀ R ₂₀ ) _n OR ₆ . In another embodiment of the invention, the R ₆ substituent in (CR ₁₀ R ₂₀ ) _n OR ₆ is hydrogen.

In another embodiment of the invention, X is R ₂ and R ₂ is (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ), such as CH (CH ₂ OH) ₂ or C (CH ₃ ) (CH ₂ OH) ₂ ; Or R ₂ is (CR ₁₀ R ₂₀ ) _{q '} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ), q' is 0 and the residue is X ₁ (CR ₁₀ R ₂₀ ) _q CH (CH ₂ OH) ₂ or X ₁ (CR ₁₀ R ₂₀ ) _q C (CH ₃ ) (CH ₂ OH) ₂ ; In other embodiments, X ₁ is oxygen or nitrogen.

In one embodiment of the invention, X is R ₂ , OR _{2 ′} , (CH ₂ ) _n NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ).

In other embodiments, X is S (O) _m R _{2 ′} , (CH ₂ ) _n NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ).

In another embodiment, X is (CH ₂ ) _n NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ).

In another embodiment, X is (CH ₂ ) _n NR ₄ R ₁₄ .

In another embodiment, X is (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ).

In one embodiment of the invention, X is R ₂ , OR _{2 ′} , (CH ₂ ) _n NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ).

Suitably, X is _{(CH 2) n NR 4 R} 14 in the case, R ₄ and R ₁₄ is C _{1 - 10} alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl-C _{1 - 4} is alkyl. Suitably, NR _{4 'R 14'} in each case independently C ₁₄ alkyl; Halogen, hydroxy, alkoxy, C (O) NR _{4 '} R _14' ; Or _{NR 4 'C (O) C} 1- ₁₀ one or more times with alkyl which may be substituted. Preferably, C ₁₄ alkyl is substituted with NR _{4 'R 14'.}

In one embodiment, R ₄ and R ₁₄ when the non-cyclized to one or more of R ₄ and R ₁₄ is hydrogen. In other embodiments, R ₄ and R ₁₄ are not both hydrogen.

In one embodiment, wherein X is (CH _{2) n} in NR ₄ R _14, R ₄ and R ₁₄ one of which is hydrogen and the other is an optionally substituted heteroaryl C ₁₄ alkyl. Suitably, the optionally substituted heteroaryl alkyl is an imidazolyl alkyl such as 1H-imidazol-2-yl-methyl group.

In another embodiment, X is _{(CH 2) n NR 4 R} 14 , and, R ₄ and R _14, when one of the heteroaryl C ₁₄ alkyl moiety, the heteroaryl ring is optionally substituted thienyl, optionally substituted pyrrolyl, Oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl and benzothiazolyl . Suitably, the heteroaryl C _{1 - 4} alkyl are selected from an optionally substituted pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, benzoxazolyl, benzimidazolyl and benzothiazolyl.

In other embodiments, when X is (CH ₂ ) _n NR ₄ R ₁₄ and one of R ₄ and R ₁₄ is a heterocyclicC _1-4 alkyl moiety, the optionally substituted heterocyclic ring is optionally substituted tetra Hydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl and morpholi Selected from the furnace. Suitably, a heterocyclic C _{1 - 4} alkyl moiety is selected from pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholino optionally substituted.

In other embodiments, when X is (CH ₂ ) _n NR ₄ R ₁₄ and R ₄ and R ₁₄ are cyclized with nitrogen to form an optionally substituted ring as described above, such rings include pyrrolidine , Piperidine, piperazine, diazepine and morpholine, but are not limited to these.

In one embodiment, where X is (CH ₂ ) _n NR ₄ R ₁₄ , R ₄ and R ₁₄ are cyclized to form an optionally substituted 5- or 6-membered heterocyclic ring as defined herein do. When the R ₄ and R ₁₄ substituents are cyclized to form a 4- to 7-membered ring, any substituent is suitably optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetero _{cyclic, (CR 10 R 20) n} N (R 10 ') C (Z) oR 7, NR 4' R 14 ', or optionally one or more times with a substituted aryl-substituted C _{1 -} is selected from ₁₀ alkyl . More specifically such substituents include phenyl, pyrrolidinyl, morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl, 2-oxo-2,3-dihydro-1H-benz Imidazol-1-yl, 5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl, ethyl, propyl, butyl, amino, methylamino and dimethyl There is amino.

In one embodiment, the X substituent is an optionally substituted 1,4'-bipipelin-1-yl ring, such as 4-methyl-1,4'-bipipelin-1-yl; 4-piperidinylamino, 4-amino-1-piperidinyl, 2,2,6,6-tetramethyl-4-piperidinyl) amino, 4-methyl-1-piperazinyl, (4-mor Polyyl) -1-piperidinyl, (4-methyl-1-piperazinyl) -1-piperidinyl, 4-ethyl-1-piperazinyl, (2-oxo-2,3-dihydro- 1H-benzimidazol-1-yl) -1-piperidinyl, 5-chloro- (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinyl, 4- (1-pyrrolidinyl) -1-piperidinyl, 4- (diphenylmethyl) -1-piperazinyl, 4-methylhexahydro-1H-1,4-diazepin-1-yl, 4 -Propyl-1-piperazinyl or 4-butyl-1-piperazinyl. In further embodiments, the X substituent is an optionally substituted 1,4'-bipipelin-1'yl ring, 4-amino-1-piperidinyl or 2,2,6,6-tetramethyl-4-piperidi Yl) amino.

In another embodiment, X is _{(CH 2) n N (R} 2 ') (R 2 ") , and, R _2' is an optionally substituted C _{1 -} when the _10-alkyl residue, the alkyl is a (CR ₁₀ R _{20) n} NR _e R _{e 'is} replaced by a, R _e and R _e' is hydrogen or an optionally substituted C _{1 -. 10} is suitably alkyl, X moiety is 3- (diethylamino) propylamino, 3- (dimethyl Amino) propyl (methyl) amino, 3- (dimethylamino) propyl (methyl) amino, 2- (dimethylamino) ethylamino, 1- (methylethyl) amino-propylamino, (1,1-dimethylethyl) aminopropyl Amino, (1-methylethyl) aminoethylamino, 2- (methylamino) ethylamino, 2-aminoethyl (methyl) amino, or 2- (dimethylamino) ethyl (methyl) amino.

In another embodiment, X is _{(CH 2) n N (R} 2 ') (R 2 ") , and, R _2' if the moiety is optionally substituted heteroaryl C _{1- 10} alkyl, the heteroaryl moiety is suitably Optionally substituted imidazole.

In one embodiment of the invention, R ₄ and R ₁₄ when the non-cyclized at least one of R ₄ and R ₁₄ may be hydrogen in the.

In one embodiment, R ₃ is 2,6-difluoro phenyl and R _{1 ′} is independently selected at each occurrence from hydrogen, fluorine or methyl; g is 1 or 2; R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b or N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b . Preferably, R ₁ is selected from C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b . In other embodiments, R _b moiety is thiazolyl, C _{1 - 10} alkyl, or is selected from optionally substituted aryl. In other embodiments, the R _b moiety is propyl or 4-fluorophenyl. In other embodiments, the R _b residue is thiazolyl.

In other embodiments, X is suitably (1H-imidazol-2-ylmethyl) amino or 4-methyl-1,4'-bipiperidin-1'-yl, 2,2,6,6-tetra Methyl-4-piperidinyl) amino, 4-amino-1-piperidinyl, 3- (diethylamino) propylamino, 3- (dimethylamino) propyl (methyl) amino, 3- (dimethylamino) propyl ( Methyl) amino, 2- (dimethylamino) ethylamino, 1-methylethyl) amino-propylamino, (1,1-dimethylethyl) aminopropylamino, (1-methylethyl) aminoethylamino, 2- (methylamino ) Ethylamino, 2-aminoethyl (methyl) amino or 2- (dimethylamino) ethyl (methyl) amino.

In one embodiment, R ₃ is 2,6-difluoro phenyl and R _{1 ′} is independently selected at each occurrence from hydrogen, fluorine or methyl; g is 1 or 2; R ₁ is _{C (Z) N (R 10} ') (CR 10 R 20) is selected from R _{v b,} R _b moieties are C _{1 - 10} alkyl or an optionally substituted aryl, preferably propyl or 4- Phenyl, or optionally substituted heteroaryl, preferably thiazolyl; X is (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ) and n is 0. In other embodiments, X is (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ), R _{2 ″} is hydrogen, n is 0 and R _{2 ′} is alkyl substituted by (CR ₁₀ R ₂₀ ) _n NR _e R _{e ′} . In further embodiments, R _e and R _{e ′} are optionally substituted C _{1 - 4} alkyl, such as methyl, ethyl, isopropyl, n- butyl, or is independently selected from t- butyl, preferably ethyl.

Other embodiments of the invention R ₁ is _{C (Z) N (R 10} ') (CR 10 R 20) v R b and, R _b is an optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 - 10} alkyl, is a (sub-group of compounds of formula I and Ia) ₁₀ alkyl group of the formula Ic _-, optionally substituted heterocyclic, and optionally substituted heterocyclic C _1. The remaining groups are the same as listed above for Formulas I and Ia.

In other embodiments of compounds of Formula (Ic), R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b , R _b is optionally substituted heteroaryl, or optionally substituted heteroaryl C _{1 - 10} is alkyl.

Suitably, the heteroaryl, heteroarylalkyl, heterocyclic and heterocyclicalkyl moieties are as defined above for Formulas I and Ia. Preferred heteroaryl rings are optionally substituted thiazolyl rings, pyridyls or thiophenes rings.

In one embodiment of the invention, Formula I, Ia and Ic, as well as in the compounds of the other formula herein R _{1 'is} hydrogen, halogen, C _{1 - 4} alkyl or halo-independently selected from _{4-alkyl-substituted} C ₁ do. In other embodiments, R _{1 ′} is independently selected from hydrogen, fluorine, chlorine, methyl or CF ₃ . In one embodiment, when R _{1 ′} is substituted at the ortho position on the phenyl ring and the second R _{1 ′} residue is also substituted on the ring, the second substituent is preferably not at another ortho position.

In one embodiment of the invention, g is 1 or 2.

Suitably, when R ₃ is an aryl moiety in one embodiment, which is a phenyl ring, the phenyl ring is independently halogen, in each case, C _{1 - 4} alkyl or halo-optionally substituted by _{4 alkyl-substituted} C ₁ It is substituted 1 or more times suitably 1-4 times. The phenyl ring may suitably be substituted at the 2, 4 or 6-position or di-substituted at the 2,4-position (eg 2-fluoro, 4-fluoro, 2,4-difluoro, 2,6 -Difluoro, 6-difluoro or 2-methyl-4-fluoro) or trisubstituted (e.g., 2,4,6-trifluoro) at the 2,4,6-position have. Preferably, R ₃ is 2,6-difluoro phenyl.

In one embodiment, R ₃ is 2,6-difluoro phenyl and R _{1 ′} is independently selected at each occurrence from hydrogen, fluorine or methyl; g is 1 or 2.

In other embodiments of the invention, Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1 The compounds of may also include the B-Non-Ar-cyc residues disclosed in US Pat. No. 6,809,199 for the X group, the disclosure of which is incorporated herein by reference.

As shown in the US 6,809,199 disclosure, Non-Ar-cyc is suitably

or

(Wherein

d is an integer having a value of 1, 2, 3 or 4;

d 'is 0 or an integer having a value of 1, 2 or 3;

d "is 0 or an integer having a value of 1, 2 or 3;

e is 0 or an integer having a value of 1, 2, 3 or 4;

e 'is 0 or an integer having a value of 1, 2 or 3;

e "is 0 or an integer having a value of 1, 2 or 3;

f is 0 or an integer having a value of 1, 2 or 3;

d + e is 2, 3, 4, 5 or 6;

d '+ e "= d;

e '+ e "= m)

Is selected from

Suitably, R _{7 ',} R ₇₇ and R _{77 "is} hydrogen, C _{1 - 6} alkyl-group, C _{2 - 6} alkenyl-group, C _{4 - 6} cycloalkyl, -C _{0 - 6} alkyl-group, N (C _{0 - 4} alkyl) (C _{0 - 4} alkyl) -C _{1 - 4} alkyl, -N (C _{0 - 4} alkyl) - group, a -N (C _{0 - 4} alkyl) (C _{0 - 4} alkyl) group, C _{0 - 3} alkyl, -CO-C _{0 - 4} alkyl-group, C _{0 - 6} alkyl, -OC (O) C _{0- 4} alkyl-group, C _{0 - 6} alkyl -C (O) -OC _{0 - 4} alkyl - group, N (C _{0 - 4} alkyl) (C _{0 - 4} alkyl) - (C _{0 - 4 alkyl) C (O) (C 0} - 4 alkyl) - group, a phenyl -C _{0 - 4} alkyl-group, pyridyl -C _{0 - 4} alkyl-group, pyrimidinyl -C _{0 - 4} alkyl-group, pyrazinyl -C _{0 - 4} alkyl-group, thiophenyl -C _{0 - 4} alkyl-group, pyrazolyl -C _{0 - 4} alkyl-group, imidazolyl -C _{0 - 4} alkyl-group, triazolyl -C _{0 - 4} alkyl-group, azetidinyl -C _{0 - 4} alkyl-group, pyrrolidinyl -C _{0 - 4} alkyl - group, isoquinolinyl -C _{0 - 4} alkyl-group, indanyl -C _{0 - 4} alkyl-group, benzothiazolyl -C _{0 - 4} alkyl-group, one to six substituents (each substituent is independently a -OH, -N (C _0-4 alkyl) (C _{0 - 4} alkyl), C _{1 -} Each independently from halogen or being) optionally substituted by any group - ₄ alkyl, C _{1 - 6} alkoxyl, C _{1 - 6} alkyl, -CO-C _{0 - 4} alkyl-, pyrrolidinyl -C _{0 - 4} alkyl Or R _{7 ′} is ═O with a bond from an absent ring hydrogen.

Suitably, B is -C _{1 - 6} alkyl _-, -C ₀ - ₃ alkyl, -OC _{0 - 3} alkyl _-, -CC ₀ - ₃ alkyl, -NH-C _{0 - 3} alkyl -, -C _0-3 alkyl -NH-C _{3 - 7} cycloalkyl _-, -C ₀ - ₃ alkyl, -N (C _{0 - 3 alkyl) -C (O) -C 0 -} 3 alkyl _-, -C ₀ - ₃ alkyl, -NH-SO ₂ -C _0-3 alkyl _-, -C ₀ - ₃ alkyl _-, -C ₀ - ₃ alkyl, -SC _{0 - 3} alkyl _-, -C ₀ - ₃ alkyl, -SO ₂ -C _{0 - 3} alkyl -, -C _{0 - 3} alkyl -PH-C _0-3 alkyl -, C _{0 - 3} alkyl, -C (O) -C _{0 - 3} alkyl is coupled, or direct.

Suitably, E ₁ is CH, N or CR ₆₆ ; Or B and E ₁ together form a double bond, ie CH═C.

Suitably, E ₂ is CH ₂ , CHR ₇₇ , C (OH) R ₇₇ NH, NR ₇₇ , O, S, -S (O)-or -S (O) _2- .

Suitably, R ₆₆ is halogen, C ₀ in each case _{- 4} alkyl, -C (O) -O (C 0 - 4 alkyl) or -C (O) -N (C _0-4 alkyl) - ( ₀ C _- from ₄ alkyl) it is independently selected.

In an alternative embodiment of the invention, Non-Ar-Cyc is

to be.

In other embodiments of the invention, Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1 The compounds of also contain the B-Non-Ar-cyc residues disclosed in WO 2004/073628 (September 2004 by Boehm et al., The disclosure of which is incorporated herein by reference above) for the X group. Include.

Another embodiment of the present invention is a compound of Formulas II and IIa represented by the following structures and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the invention is a compound of formula III or IIIa, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

<Formula IIa>

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₆ are independently selected from nitrogen or CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Between the compounds of Formulas I and Ia, Formulas II and IIa, and Formulas III and IIIa to Formulas V and Va, the ring substitution of the R ₁ group as well as the nitrogen of the pyridyl ring, such as G ₅ and G ₆ variable groups, It should be recognized that there is a difference in ring position. In the case of the compounds of the formulas (III) and (IIIa) to (V) and (Va), the remaining variable groups all have the same meanings as described for the compounds of the formulas (I) and (Ia) and the like.

Another aspect of the invention is a compound of formula IV or IVa, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₆ are independently selected from nitrogen or CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Representative examples of compounds of Formulas IV and IVa include

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] benzoic acid,

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-propylbenzamide,

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1-methylethyl) benzamide,

N-cyclopropyl-4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] benzamide,

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (4-fluorophenyl) benzamide,

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-1,3-thiazol-2-ylbenzamide

Another aspect of the invention is a compound of formula V or Va, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are independently selected from nitrogen or carbon;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₆ are nitrogen or CH, provided that only one of G ₅ or G ₆ is nitrogen and the other is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the invention is a compound of formula VI or VIa, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are independently selected from nitrogen or CH;

G ₃ is CH ₂ ;

G ₄ is CH;

One of G ₅ , G ₆ , G ₇ and G ₈ is nitrogen, and the other is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

It should be appreciated that there are differences in the ring positions of the two nitrogens of the pyrimidine ring as well as the ring substitution of the R ₁ group between the compounds of formulas I and Ia, II and IIa, and VI-VIi. In the case of compounds of formulas VI-VIi, all remaining variable groups have the same meanings as described for compounds of formulas I and Ia and the like.

Another aspect of the invention is a compound of formula VIb or VIc, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₆ are nitrogen;

G ₇ and G ₈ are CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the invention is a compound of formula VId or VIe, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are independently selected from nitrogen or CH;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₆ and G ₈ are nitrogen;

G ₅ and G ₇ are CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the invention is a compound of formula VIf or VIg, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₈ are nitrogen;

G ₆ and G ₇ are CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the invention is a compound of formula VIh or VIi, and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

Where

G ₁ and G ₂ are nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

G ₅ and G ₇ are nitrogen;

G ₅ and G ₈ are CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Another aspect of the present invention are compounds of Formulas A and A1, and their pharmaceutically acceptable salts, solvates or physiologically functional derivatives.

Where

G ₁ and G ₂ are independently nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

Y is C (R _x ) (R _z ), C (O), N (R _z ), N (R _w ) C (R _y ) (R _z ), oxygen, OC (R _y ) (R _z ), S (O) _m or S (O) _m C (R _y ) (R _z );

R _x is hydrogen, C _{1 - 2} alkyl, N (R _{v) 2,} hydroxy, thio, C _{1 - 2} alkoxy or S (O) _m C _{1- 2} alkyl;

R _y is hydrogen or C _{1 -} and _2-alkyl;

R _{z 'is} hydrogen or C _{1 -} and _2-alkyl;

R _w is hydrogen or C _{1 -} and _2-alkyl;

R _v is hydrogen or C _{1 -} is independently selected from _2-alkyl;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

The present invention relates to novel compounds of Formulas (A) and (Al) or pharmaceutically acceptable derivatives thereof. As will be readily appreciated, there is a difference in linker Y between compounds of Formulas A and A1. Groups such as R ₁ , R ₂ and R ₃ are the same in each of the two compounds. For the purposes of the present invention, everything applicable to formula (I) is also applicable to formula (A) unless otherwise indicated.

Another aspect of the present invention are compounds of formulas B and B1, and their pharmaceutically acceptable salts, solvates or physiologically functional derivatives.

Where

G ₁ and G ₂ are independently nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

Y is C (R _x ) (R _z ), C (O), N (R _z ), N (R _w ) C (R _y ) (R _z ), oxygen, OC (R _y ) (R _z ), S (O) _m or S (O) _m C (R _y ) (R _z );

R _x is hydrogen, C _{1 - 2} alkyl, N (R _{v) 2,} hydroxy, thio, C _{1 - 2} alkoxy or S (O) _m C _{1- 2} alkyl;

R _y is hydrogen or C _{1 -} and _2-alkyl;

R _{z 'is} hydrogen or C _{1 -} and _2-alkyl;

R _w is hydrogen or C _{1 -} and _2-alkyl;

R _v is hydrogen or C _{1 -} is independently selected from _2-alkyl;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

As will be readily appreciated, there is a difference in linker Y between the compounds of Formulas B and B1 and of Formulas II and IIa. Groups such as R ₁ , R ₂ and R ₃ are the same in each of the two compounds. For the purposes of the present invention, everything applicable to formula (II) is also applicable to formula (B) unless otherwise indicated.

In other aspects of the invention, in all other formulas of the invention, i.e., in formulas III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, etc., the linker Y may be located in the same position in a similar manner. The groups such as R ₁ , R ₂ and R ₃ will each be identical to each other in all compounds.

Another aspect of the present invention are compounds of formulas VIII and VIIIa, and their pharmaceutically acceptable salts, solvates or physiologically functional derivatives.

Where

G ₁ and G ₂ are independently nitrogen or CH, but both G ₁ and G ₂ are not nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

In another embodiment of the invention, the X group may also be a B-Non-Ar-cyc residue as described.

In another embodiment of the invention, for the compounds of formulas VIII and VIIIa, and the remaining formulas, the X group is also disclosed in WO 2004/073628 (September 2004 by Boem et al .; the disclosure of which is incorporated herein by reference. X residues disclosed in, incorporated by reference.

For the purposes of the present invention, the main chain containing G ₁ and G ₂ residues is a (R ₁ and R _{1 ′} ) substituent on the phenyl, pyridyl and pyrimidine rings at the C ₄ position of the pharmacological end, X at the C ₂ position. It will have a numbering system that allows to distinguish between groups and R ₃ substituents at the N ₈ position.

The groups such as R ₁ , R ₂ , R _x , X and R ₃ are identical to each other in the formula itself, for example in the compounds of the formulas VIII and VIIIa. For the purposes of the present invention, everything applicable to formula (VIII) is also applicable to formula (VIIIa) unless otherwise indicated.

It is recognized that there are differences between the compounds of formulas (I) and (Ia), and the compounds of formulas (VIII) and (VIIIa), wherein the G ₁ and G ₂ residues are independently carbon or nitrogen. For the purposes of the present invention, the remaining compounds of Formulas II and IIa, III and IIIa, IV and IVa, V and Va, VI, and VIa to VIi are also

,

May have the same pharmacological end chain.

This describes the C ₄ substitution on the pharmacologically active backbone from a compound of formula (II) and (IIa), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, represented by the structure:

Where

G ₁ and G ₂ are independently nitrogen or CH, but both G ₁ and G ₂ are not nitrogen;

G ₃ is CH ₂ ;

G ₄ is CH;

R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ;

R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ;

R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and;

X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ;

X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ;

R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —;

R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring;

R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues;

R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and;

R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues;

A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl;

A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety;

R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen;

R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms;

R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH);

R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl;

R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 -4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted);

R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form;

g is 0 or an integer having a value of 1, 2, 3 or 4;

n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10;

m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

q is 0, or an integer having a value of 1 to 10;

q 'is 0, or an integer having a value of 1 to 6;

t is an integer having a value of 2 to 6;

v is 0 or an integer having a value of 1 or 2;

v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2;

Z is independently selected at each occurrence from oxygen or sulfur.

Thus, compounds substituted with a G1 / G2 pharmacologically active main chain of carbon or nitrogen at positions C ₄ from Formulas III and IIIa will be considered compounds such as Formulas X and Xa.

It is to be understood that the present invention includes all combinations of the specific groups and preferred groups described above. In addition, the present invention provides a general formula (I) in which a specific group or parameter, such as R ₅ , R ₆ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , p, n or q, may appear more than once. It will be understood to include compounds of In such compounds, it will be understood that each group or parameter is independently selected from the listed values. If any variable appears more than once in the formula (as described herein), its definition in each case is separate from its definition in all other cases.

Certain compounds according to the present invention include the compounds mentioned in the Examples and their pharmaceutical derivatives.

As used herein, the term “pharmaceutically acceptable” means a compound suitable for pharmaceutically and veterinary use. Salts and solvates of the compounds of the present invention suitable for use in medicine are those in which the counterions or related solvents are pharmaceutically acceptable. However, salts and solvates having pharmaceutically unacceptable counterions or related solvents are also included within the scope of the present invention, which are for example used in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates. Used as intermediate.

As used herein, the term “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable compound of the invention that can provide (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof, when administered to a recipient. Acceptable salts, solvates or prodrugs such as esters. Such derivatives can be recognized by those skilled in the art without undue experimentation. However, Burger's Medicinal Chemistry and Drug Discovery, 5 ^th Edition, Vol. 1: Principles and Practice (incorporated herein by reference to the extent that the derivatives are taught by reference) may be referred to. In one embodiment, pharmaceutically acceptable derivatives are salts, solvates, esters, carbamate and phosphate esters. In other embodiments, pharmaceutically acceptable derivatives are salts, solvates and esters. In another embodiment of the invention, the pharmaceutically acceptable derivatives are salts and esters, in particular salts.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts and / or administered as pharmaceutically acceptable salts. A review of suitable salts is given in Berge et al, J. Pharm. Sci., 1977, 66, 1-19.

Typically, pharmaceutically acceptable salts can be readily prepared with the appropriate acid or base as appropriate. Salts can be precipitated out of solution and collected by filtration or recovered by evaporation of the solvent.

Salts of the compounds of the present invention include, for example, acid addition salts formed by reacting an acid with a nitrogen atom present in a compound of formula (I). Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Suitable addition salts are formed from acids which form non-toxic salts, for example acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromide, calcium edetate, chamlates, Carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, edisylates, estoleates, ecylates, ethanesulfonates, formates, fumarates, glutceptates, gluconates, glutamate, Glycolyl Arsanilate, Hexyl Resorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydrogen Phosphate, Hydroiodide, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Lau Rate, Maleate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitre , Methylsulfate, monopotassium maleate, mucate, naphsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate, phosphate / Diphosphates, pyruvates, polygalacturonates, saccharides, salicylates, stearates, subacetates, succinates, sulfates, tannates, tartrates, theoclates, tosylates, triethiodes, Trifluoroacetate and valerate.

Pharmaceutically acceptable base salts are ammonium salts such as trimethylammonium salts, alkali metal salts such as salts of sodium and potassium, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as primary and secondary And salts with tertiary amines such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

One skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. These complexes are known as "solvates." As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in the present invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents used for the purposes of the present invention cannot impair the biological activity of the solute. Examples of suitable solvents are water, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents are water, ethanol and acetic acid. Most preferably, the solvent used is water. Complexes with water are known as "hydrates". Solvates of the compounds of the invention are included in the scope of the invention.

As used herein, the term “prodrug” means a compound that is converted into its active form in the body, for example by hydrolysis in the blood, to produce a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130] (these documents are each incorporated herein by reference). Included by reference).

Prodrugs are any covalently bonded carriers that, when administered to a patient, release the compound of formula (I) in vivo. Prodrugs are generally prepared by modifying functional groups in such a way that the site of modification is cleaved by conventional means or in vivo to provide the parent compound. Prodrugs include, for example, compounds of the present invention that are bound to any group that is cleaved when the hydroxy or amine group is administered to a patient to form a hydroxy or amine group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester and the like can be used. The ester is itself active and / or can be hydrolyzed under in vivo conditions in the human body. Suitable in vivo hydrolyzable ester groups that are pharmaceutically acceptable include those that readily decompose in the human body to release the parent acid or salt thereof.

As used herein, “optionally substituted” includes halogens such as fluorine, chlorine, bromine or iodine, unless specifically defined otherwise; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy, such as methoxy or ethoxy; Halo-substituted C _{1 - 10} alkoxy; S (O) _m alkyl such as methylthio, methylsulfinyl or methylsulfonyl; A ketone (-C (O)) or an aldehyde _{(-C (O) R 6 '} ), for example C (O) C _{1- 10} alkyl, or C (O) aryl (wherein, R _6' is hydrogen, C _{1 - 10} alkyl, C _3-7 cycloalkyl, heterocyclyl, heterocyclyl C _1-10 alkyl, aryl, aryl _1-10 alkyl, heteroaryl or heteroaryl-C _{1 - 10} alkyl, and, R _{6 'is} a moiety other than hydrogen itself is a halogen, in each case independently; hydroxy; hydroxy-substituted alkyl, C _{1 - 4 alkoxy; S (O) m C 1-} 4 alkyl, amino, mono- or disubstituted with C _{1 - 4} alkyl amino; C _{1 - 4} alkyl, or may be by a CF _3, optionally substituted once or twice); C (O) OR _{6 '} ; NR _{4 'R 14'} (wherein, R _{4 'and} R _14' are each independently hydrogen or C ₁₄ alkyl, such as amino or one C ₁₄ alkyl-substituted or disubstituted, or R _{4 'R 14'} Can be cyclized with the nitrogen to which they are attached to form a 5- to 7-membered ring, optionally containing additional heteroatoms selected from O / N / S); C _{1 - 10} alkyl, such as methyl, ethyl, propyl, isopropyl, t- butyl and the like; C _{3 - 7} cycloalkyl or C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl group such as cyclopropyl, cyclobutyl or cyclopropylmethyl; Halo-substituted C _1-10 alkyl, such as CF ₂ CF ₂ H or CF ₃ ; Optionally substituted aryl such as phenyl, or an optionally substituted aryl C _{1 - 4} alkyl, such as benzyl or phenethyl (these aryl containing moieties may also halogen, in each case independently; hydroxy; hydroxy-substituted alkyl; C _{1 - 4} alkoxy; S (O) _m C _1-4 alkyl, amino, mono- or disubstituted with C _{1 - 4} alkylamino; C _{1 - 4} alkyl or may be substituted once or twice by a CF ₃₎ and It means the same group.

Suitable pharmaceutically acceptable salts are known to those skilled in the art and include salts formed with organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid. , Malic acid, glutamic acid, aspartic acid, oxaloacetic acid, alkyl sulfonic acid derivatives such as methanesulfonic acid or ethanesulfonic acid, arylsulfonic acid derivatives such as p-toluenesulfonic acid, m-toluenesulfonic acid, benzenesulfonic acid, camphor sulfonic acid, 4-chlorobenzenesulfonic acid , 4-bromobenzenesulfonic acid, 4-phenylbenzenesulfonic acid, naphthalenesulfonic acid or naphthalenesulfonic acid, phenylacetic acid, mandelic acid, salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted cinnamic acid ( For example, cinnamic acid substituted with phenyl, methyl, cyano, methoxy or halo such as 4-methyl and 4-methoxy cinnamic acid), ascorbic acid, oleic acid, naphthoic acid, Loxynaphthoic acid (eg 1- or 3-hydroxy-2-naphthoic acid), naphthaleneacrylic acid (eg naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydric And those formed from oxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg 1,4-benzenediacrylic acid) and isethionic acid.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as salts of sodium and potassium, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexyl amine and N-methyl-D -Salts with glucamine.

In addition, pharmaceutically acceptable salts of compounds of formula (I) may be formed with pharmaceutically acceptable cations, for example where the substituents comprise carboxy moieties. Suitable pharmaceutically acceptable cations are known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

As used herein, the term "halo" or "halogen" means halogen, chloro, fluoro, bromo and iodo.

As used herein, the term "C _{1 - 10} alkyl" or "alkyl" or "alkyl _1-10" is meant both linear and branched hydrocarbon chain containing the specified number of carbon atoms and, for example, C _1-10 Alkyl means a straight or branched alkyl chain having at least 1 and at most 10 carbon atoms, unless the chain length is otherwise defined. Examples of "alkyl" as used herein include methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, sec-butyl, tert-butyl or t-butyl and hexyl, and the like. It is not limited to.

The term "alkenyl" as used herein refers to a linear or branched hydrocarbon chain containing a certain number of carbon atoms and one or more double bonds. For example, C _{2 - 6} alkenyl and refers to linear or branched alkenyl group containing carbon atoms and at least one double bond of less than six or more than two. Examples of "alkenyl" as used herein include ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3- Methylbut-2-enyl, 3-hexenyl, 1,1-dimethylbut-2-enyl and the like, but are not limited to these.

The term "alkoxy" as used herein refers to a straight or branched chain alkoxy group containing a certain number of carbon atoms. For example, C _{1 -} to ₆ alkoxy means a straight or branched chain alkoxy containing up to 6 carbon atoms in one or more of them. Examples of "alkoxy" as used herein include methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop -2-oxy, pentoxy and hexyloxy, but are not limited to these.

As used herein, the term “cycloalkyl” refers to a cyclic radical, such as a non-aromatic hydrocarbon ring, containing a certain number of carbon atoms. For example, C _{3 - 7} cycloalkyl has at least 3 non-containing ring carbon atoms of less than 7; means an aromatic ring. Representative examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

As used herein, the term "cycloalkenyl" means a cyclic radical such as a non-aromatic hydrocarbon ring containing a certain number of carbon atoms, preferably 5 to 7 carbons and having at least one bond, and cyclopentenyl , Cyclohexenyl and the like, but are not limited to these.

As used herein, the term "alkenyl" refers to straight or branched chain radicals having 2 to 10 carbon atoms in all cases unless the chain length is otherwise defined, ethenyl, 1-propenyl, 2-propenyl , 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, but are not limited to these.

As used herein, the term "aryl" refers to phenyl, naphthyl and indene.

As used herein, the terms "heteroaryl ring", "heteroaryl moiety" and "heteroaryl" refer to monocyclic 5- to 7-membered unsaturated hydrocarbon rings containing one or more heteroatoms selected from oxygen, nitrogen and sulfur. it means. Examples of heteroaryl rings include furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxthiadiazolyl, triazolyl, Tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and uracil. As used herein, the terms “heteroaryl ring”, “heteroaryl moiety” and “heteroaryl” also refer to a fused aromatic ring comprising one or more heteroatoms selected from oxygen, nitrogen and sulfur. Fused rings may contain 5 or 6 ring atoms each. Examples of fused aromatic rings include indolyl, isoindoleyl, indazolyl, indolinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, iso Quinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl and phthalazinyl, but are not limited to these.

As used herein, the terms "heterocyclic ring", "heterocyclic residue" and "heterocyclyl" refer to nitrogen, oxygen, sulfur or oxidized sulfur residues such as S (O) _m (m is 0, or 1 or Monocyclic 3- to 7-membered saturated or non-aromatic unsaturated hydrocarbon ring containing one or more heteroatoms selected from (which is an integer having a value of 2). The terms "heterocyclic ring", "heterocyclic moiety" and "heterocyclyl" also denote saturated or partially unsaturated fused rings in which one of the rings may be aromatic or heteroaromatic. The fused ring may each have 4 to 7 ring atoms. Examples of heterocyclyl groups include saturated or partially saturated forms of heteroaryl residues as defined above, such as tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized forms of sulfur residues), azedes Pin, diazepine, aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5-yl, already Dazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino, including oxidized forms of sulfur residues It is not limited.

The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" as used herein, unless otherwise indicated, is a C ₁ attached to an aryl, heteroaryl or heterocyclic moiety (also as defined above). ₄ refers to an alkyl (as defined above).

As used herein, the term "sulfinyl" refers to the oxide S (O) of the corresponding sulfide, the term "thio" refers to sulfide, and the term "sulfonyl" refers to a fully oxidized S (O) ₂ residue. Indicates.

As used herein, the term “aroyl” means C (O) Ar, wherein Ar is phenyl, naphthyl, or aryl alkyl derivatives (including benzyl and phenethyl, etc.) as defined above.

The term "alkanoyl" as used herein refers to C (O) C _{1- 10} alkyl (wherein alkyl is as defined above).

As used herein, the term “optionally” means that the event (s) described below may or may not occur, and includes both event (s) and event (s) that do not occur.

As used herein, the term “substituted” refers to substitution with the substituent (s) mentioned, and multiple substitutions are permitted unless stated otherwise.

It is to be understood that the present invention includes all combinations of the specific groups and preferred groups described above. In addition, the present invention relates to compounds of formula (I) in which certain groups or parameters, such as R ₅ , R ₆ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , p, n or t, may appear one or more times. It will be understood to include the compound. In such compounds, it will be appreciated that each group or parameter is independently selected from the listed values. If any variable appears more than once in the formula (as described herein) its definition in each case is separate from its definition in all other cases.

With regard to stereoisomers, the compounds of the formulas of the present invention may have one or more asymmetric carbon atoms and may appear as racemates, racemic mixtures and individual enantiomers or diastereomers. All such isomeric forms and mixtures thereof are included in the present invention.

Cis (E) and trans (Z) isomers may also appear. The present invention includes the individual stereoisomers of the compounds of the present invention and suitably includes their individual tautomeric forms with mixtures thereof.

Separation of diastereomers or cis and trans isomers can be carried out by conventional techniques such as fractional crystallization, chromatography or HPLC. Stereoisomeric mixtures of the formulations may also be prepared from the corresponding optically pure intermediates, as appropriate, or corresponding to the cleavage of the corresponding racemate (eg HPLC) or a suitable optically active acid or base using a suitable chiral support. Can be prepared by fractional crystallization of diastereomeric salts formed by the reaction of racemates.

In addition, some crystalline forms of the compounds of the formulas described herein may exist as polymorphs (included in the present invention).

Exemplary compounds of the compounds of the present invention include racemate or optically active forms of the compounds of the embodiments of the present invention, and pharmaceutically acceptable salts thereof.

Compounds of the invention can be prepared by a variety of methods, including standard chemistry. Any of the above defined variables will continue to have the meanings previously defined unless otherwise indicated. Illustrative examples of general synthetic methods are listed below, followed by the preparation of certain compounds of the invention in the Examples.

Manufacturing method

Compounds of Formulas I and Ia, II and IIa, II and IIIa, IV and IVa, V and Va, VI, VIa to VII, VIII, VIIIa, IX, IXa, A, A1, B and B1 are described in the synthetic procedures described herein. It can be obtained by applying. The provided synthetic methods suitably produce compounds of the formula of the present invention having several different R ₁ , R ₂ , X and R ₃ reactors which achieve affinity for the reactions outlined herein using any protected substituents. It can be applied to. The deprotection reaction entailed in this case provides compounds with the following generally disclosed characteristics. Although specific formulas with specific substituents are shown herein, the synthesis can be applied to all formulas and all substituents of the invention.

Once the essential part has been established, standard techniques for the interconversion of functional groups known in the art may be applied to formulas I and Ia, II and IIa, II and IIIa, IV and IVa, V and Va, VI, VIa to VII, Further compounds of VIII, VIIIa, IX, IXa, A, A1, B and B1 can be prepared. For example, C (O) NR ₄ R ₁₄ is formed by heating with HNR ₄ R _{14 in} CH ₃ OH in the presence or absence of a catalytic or stoichiometric metal cyanide or aluminum trimethyl, for example NaCN, from CO ₂ CH ₃ . and; From OH in bases such as triethylamine and pyridine, for example using ClC (O) R ₆ to form OC (O) R ₆ ; Alkyl isothiocyanate, or thiocyanic acid and ClC (S) NR ₄ R ₁₄ from NHR ₁₀ to form NR ₁₀ -C (S) NR ₄ R ₁₄ ; Alkyl or aryl chloroformate from NHR ₁₀ to form NR ₁₀ C (O) OR ₆ ; From NHR _{10 with} isocyanate, for example R ₄ N═C═O, to form NR ₁₀ C (O) NR ₄ H; Treatment with Cl-C (O) R ₆ in pyridine from NHR ₁₀ to form NR ₁₀ -C (O) R ₆ ; C (= NR ₁₀ ) NR ₄ R ₁₄ is formed by heating in alcohol with H ₃ NR _{10 +} OAc- from C (NR ₄ R ₁₄ ) S; Forming C (NR ₄ R ₁₄ ) SR ₆ using R ₆ -I in an inert solvent such as acetone from C (S) NR ₄ R ₁₄ ; NR ₁₀ SO ₂ R ₇ is formed from NHR ₁₀ by heating in ClSO ₂ R ₇ and a base such as pyridine; NR ₁₀ C (O) R ₆ to Lawesson reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide] Treating to form NR ₁₀ C (S) R ₆ ; And using triflic anhydride and a base from NHR ₁₀ form an NR ₁₀ SO ₂ CF _{3 (wherein, R 6, R 10, R} 4 and R ₁₄ are as defined in formula (I) of the present invention).

R _1, R ₂ and R ₃ groups of the precursor may be a different R _1, R ₂ and R ₃ groups which are interconvertible by applying standard techniques for functional group interconversion. For example, the moiety is a halo-case ₁₀ alkyl, which C ₁ corresponding to the reaction with a suitable azide _{salt-substituted} C ₁ can be converted to the _10-alkyl N _3, C ₁ which corresponds in accordance with the then _case- It can be reduced to the _10-alkyl NH ₂ compound, and then _{R 7 S (O) 2 X} '( here, X' is halo, for example chloro-Im) and C ₁ corresponding to the reaction _{- 10} alkyl, NHS (O) ₂ R ₇ compounds can be obtained.

Alternatively, the moiety is a halo-case ₁₀ alkyl, which amine R ₄ R ₁₄ NH and the reaction to the corresponding C ₁ to _- substituted C _{1 10} alkyl, NR ₄ R generate the ₁₄ compound, or an alkali metal salt of R ₇ SH It may produce compound ₁₀ alkyl, SR _{7 -} and C ₁ in response to correspond.

As mentioned above, it may be desirable to derivatize the reactive functionalities of the molecules participating in the reaction during the synthesis of the compounds of the present invention so that unwanted side reactions do not occur. Functional groups such as hydroxy, amino and acid groups are usually protected with suitable groups, which can preferably be easily removed. Conventional protecting groups suitable for use with hydroxyl groups and nitrogen groups are known in the art and are described in a number of references, for example, in Protecting Groups in Organic Synthesis, Greene et al., John Wiley & Sons, New York, New York. York, (2nd edition, 1991 or earlier 1981 version). Suitable examples of hydroxyl protecting groups include ether forming groups such as benzyl, and aryl groups such as tert-butoxycarbonyl (Boc), silyl ethers such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers such as variable There is methyl linked by an alkyl chain (CR ₁₀ R ₂₀ ) _n connecting the groups. Amino protecting groups can be benzyl, aryl such as acetyl and trialkylsilyl groups. Carboxylic acid groups are usually protected by conversion to esters which can be readily hydrolyzed, for example trichloroethyl, tert-butyl, benzyl and the like.

Pharmaceutical acid addition salts of the compounds of various formulas described herein may be obtained by known methods, for example by treatment with an appropriate amount of acid in the presence of a suitable solvent.

Exemplary preparations of the compounds of the invention are shown in the following schemes. For the purposes of the present invention, the compounds of Schemes I and II are represented using S-methyl, or S (O) ₂ -methyl groups, which are considered to be representative S (O) _m -R _g groups, as described below.

The preparation of compounds of formula (Ia) can be accomplished via compound (2), which in turn can be constructed from aldehyde (1) shown in Scheme 1. The leaving groups in Scheme 1 and elsewhere (described as LG, leaving group 1 (LG1) and LG2) can be independently selected from -Cl, -Br, -I or -OTf, which groups are known in the art According to the established method (eg, a method of treating -OH compound with POCl ₃ ), it can be arranged through modification of another functional group (eg -OH).

Method A is for the conversion of compound (1) to compound (2). Compound (1) may be prepared from an olefin former such as bis (2,2,2-trifluoroethyl)-(methoxycarbonylmethyl) -phosphonate, or an acylating agent such as acetic anhydride, melumic acid or acetyl chloride. Treatment with amine R ₃ NH ₂ in the presence gives compound (2). Bis (2,2,2-trifluoroethyl) (methoxycarbonylmethyl) phosphonate is used as the olefin forming reagent, and bis (2,2,2-trifluoroethyl is used as an alternative cyclization reagent. )-(Ethoxycarbonylmethyl) phosphonate, bis (2,2,2-trifluoroethyl)-(isopropoxycarbonyl-methyl) phosphonate, (diethoxy-phosphoryl) -methyl acetate Ester, (diisopropoxy-phosphoryl) -acetic acid methyl ester, (diphenyloxy-phosphoryl) -acetic acid methyl ester, (diethoxy-phosphoryl) -acetic acid ethyl ester, (diisopropoxy-phosphoryl) Acetic acid ethyl ester, or (diphenyloxy-phosphoryl) -acetic acid ethyl ester, but is not limited to these. To complete the reaction, elevated temperature (reflux or microwave irradiation), extended reaction time (overnight or 24 hours) and the presence of triethyl amine or diisopropyl ethyl amine or NaH (or Na) may be required. The reaction solvent can be various organic solvents such as chloroform, methylene chloride, acetonitrile, toluene, DMF, n-methylpyrrolidine, DCM, THF, toluene, DMSO, or combinations thereof. The reaction gave triethylamine as the base, and other suitable bases may include, but are not limited to, pyridine, diisopropyl ethyl amine or pyrrolidone, or combinations thereof.

The reaction temperature of this particular step in the scheme may vary from room temperature to more than 100 ° C, ie the reflux temperature of the solvent. Alternatively, the reaction process step can be carried out under suitable microwave conditions.

Method B relates to the placement of the -X group [for example, compound (2) → (3), compound (6) → (Ia), or compound (5) → (4)]. This may or may not require a first conversion of sulfide (-SMe) to sulfoxide (-SOMe) or sulfone (-SO ₂ Me). This conversion can be achieved with high yield and purity using meta-chloroperoxybenzoic acid (mCPBA). Oxidation methods suitable for use herein include obtaining sulfoxides or sulfones, or a mixture of both, using one or two equivalents of meta-chloroperoxybenzoic acid (mCPBA) or oxone®. Oxidation of sulfides to sulfoxides or sulfones can also be characterized by OsO ₄ and catalytic tertiary amine N-oxides, hydrogen peroxide, hydrogen peroxide / NaWO ₄ , and other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, and Potassium sulfate, sodium hypochlorite. Subsequent substitution of the sulfone group -SO ₂ Me (also all the substitution reactions mentioned below can be carried out using sulfide-SMe or sulfoxide -SOMe) is carried out using a suitable nucleophile containing unit -X (e.g. , Amines, alcohols). Substitution with amines is usually carried out with excess amine in N-methylpyrrolidine (Barvian et al., J. Med. Chem. (2000), 4606-4616). A wide range of primary amines achieve this reaction in good yields. In some cases (eg for O-substitution), the anion of the nucleophile is prepared using a base in DMF (or DMSO) (usually sodium hydride) and then added to the sulfone. The yield of this reaction is usually lower. The sulfones are primary and secondary at different temperatures, depending on the degree of nucleophilicity of the amine, without further base catalysis, preferably in polar aprotic solvents (such as N-methyl pyrrolidin-2-one (NMP), etc.). It may be substituted by alkylamine. For example, the substitution of sulfone with ethanolamine in NMP takes place within 30 minutes at 65 ° C., and even more masked amines such as tris (hydroxymethyl) -aminomethane have elevated temperature and extended reaction time (80 ° C., 24 ° C.). Reaction time over time). Sulfones are also substituted by primary or secondary amines with additional non-nucleophilic bases (eg, DIPEA) at different temperatures depending on the degree of nucleophilicity of the amine in aprotic solvents such as DCM, CH ₃ CN, NMP Can be.

Sulfones may also be substituted with substituted arylamines or heteroarylamines at elevated temperatures, which sometimes requires forming aryl or heteroarylamines with sodium hydride, or other suitable base in DMSO. In addition, sulfones can be readily substituted with aluminum salts of aryl or heteroarylamines as already described in the patent document WO 99/32121, the disclosure of which is incorporated herein by reference in its name. Likewise, sulfones may be substituted with aryl or heteroaryl or alkyl thiols or alkyl or aryl or heteroaryl alcohols. Analogs containing sulfones with X substituents may be substituted with sodium alkoxides in alcohols or alternatively generated from alcohols or phenols using suitable bases such as sodium, NaH or sodium bistrimethylsilyl amide in polar aprotic solvents such as DMSO It may be substituted with a reactive alkoxide or phenoxide nucleophile which may be, or proceeds to the forward reaction. Similarly, sulfones can be substituted with carbon nucleophiles. Suitable carbon nucleophiles include aryl Grignard reagents, alkyl Grignard reagents or related organometallics such as organic lithium, zinc, tin, copper or boron. These reactions may in some cases require the action of transition metal catalysts (eg Pd or Ni catalysts).

Method C is for coupling to a suitable aryl group which converts compound (3) to a compound of formula (la) (or compounds (2) to (6)). Such modifications can be carried out using boronic acid (eg C1A) or the like under Suzuki cross-coupling conditions using a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0).

Alternatively, the cross-coupling may be aryl or heteroaryl organozinc (eg aryl / heteroaryl-ZnBr, aryl / heteroaryl-ZnCl, aryl / heteroaryl-Zn-R ₁ ), organocopper [eg , (Aryl / heteroaryl) ₂ -CuLi], organotin [eg, aryl / heteroaryl-Sn (CH ₃ ) ₃ , aryl / heteroaryl-Sn (CH ₂ CH ₂ CH ₂ CH ₃ ) ₃ ] ( For example, C1C) or other organometallic reagents known in the art (eg, C1B) (see, eg, Solberg, J .; Undheim, K. Acta Chemica Scandinavia 1989, 62-68). This can be done using

Method D comprises a precursor (e.g. acidic group -CO ₂ H, ester group -CO ₂ Me) in which the compound (2) (or compound (3) or (7)) and a structural formula are suitable for the final substituent R ₁ of formula (Ia) It is about the coupling of the aryl group which has. Such modifications can be carried out or protected by boronic acid (eg D1A) under Suzuki coupling conditions (THF / H ₂ O and K ₂ CO ₃ ) using a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0). Acid (e.g., D1C, D1E) and the like. If desired, these Suzuki coupling reactions can be carried out under microwave conditions. Boronic acid (D1A or D1E) or ester is an aryl halide and 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-di Aryl halides using palladium-catalyzed coupling of oxaborolane, or using a Grignard reagent such as isopropylmagnesium bromide followed by trialkylborate (eg triethylborate) in a suitable solvent such as THF It can be synthesized by the metal potential of.

Suitably, the arylboronic acids or their corresponding boronic acid esters are aryl-boronic acid or aryl-boronic acid esters; For example, aryl B (OH) _2, aryl -B (OC _{1 - 4} alkyl) _2, or Wherein R ₁ , R ₁₀ and R ₂₀ are as defined herein for the compound of Formula I and r is an integer having a value of 2-6.

Coupling conditions include the use of a suitable solvent. Such solvents include, but are not limited to, dioxane, THF, DMF, DMSO, NMP, acetone, water, or combinations or mixtures thereof. Preferably, the solvent is THF / H ₂ O or dioxane / H ₂ O.

Coupling conditions also include the presence of a catalytic amount of catalyst, such catalysts include tetrakis (triphenylphosphine) -palladium (0), PdCl ₂ , Pd (OAc) ₂ , (CH ₃ CN) ₂ PdCl ₂ , Pd (dppf) ₂ , or [1,1′-bis (diphenylphosphino) -ferrocene] -dichloropalladium (II).

The coupling reaction may or may not require the presence of a base. Suitable bases include, but are not limited to, NaHCO ₃ , KHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , KOAc, or combinations or mixtures thereof. Preferably, the bases are K ₂ CO ₃ and KOAc.

The coupling reaction may or may not require heating. The heating can be carried out in a standard oil bath or by microwave irradiation and the temperature can vary from room temperature to more than 100 ° C., ie at the reflux temperature range of the solvent. The coupling reaction may or may not require a sealed reaction vessel, and the internal pressure may vary in the range of 1 to 100 atmospheres.

Aryl or heteroaryl boronic acids or ester intermediates containing the R ₁ residue used in the Suzuki coupling reaction may or may not be commercially available and may be prepared using methods of the appropriate literature known to those who have been properly trained. . Examples of such methods include aryl halides and palladium of 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane Metal catalysts of the aryl halides using, but not limited to, Grignard reagents such as isopropylmagnesium bromide followed by trialkylborate (eg triethylborate) in a catalyzed coupling or suitable solvent. Do not. These solvents include CH ₂ Cl ₂ , chloroform, CH ₃ CN, benzene, THF, hexane, ethyl ether, tert-butyl methyl ether, DMSO, DMF, toluene, n-methyl-pyrrolidine, dioxane, but these It is not limited to. The reaction temperature may vary from -78 ° C to more than 100 ° C, ie in the reflux temperature range of the solvent. Alternatively, this reaction process step may or may not be performed under suitable microwave irradiation conditions. This reaction may or may not require a sealed reaction vessel, and the internal pressure may vary in the range of 1 to 100 atmospheres.

Alternatively, the cross-coupling may be aryl or heteroaryl organozinc, organocopper, organotin (eg D1B) or other organometallic reagents (eg D1D) known in the art (eg, literature (Solberg, J .; Undheim, K. Acta Chemica Scandinavia 1989, 62-68). If a protected precursor (eg D1C, D1D, D1E) is used, a suitable deprotection reaction is carried out.

This coupling reaction can be carried out with aryl or heteroaryl organozinc (eg aryl-ZnBr, R ₁ -ZnCl, aryl-Zn-aryl), organocopper [eg (aryl) _2- CuLi], organotin ( For example, aryl-Sn (CH ₃ ) ₃ , aryl-Sn (CH ₂ CH ₂ CH ₂ CH ₃ ) ₃ ] or other organometallic reagents can be used to produce cross-coupling products. Preferred aryl organozinc (eg aryl-ZnBr, R ₁ -ZnCl, aryl-Zn-aryl), organocopper [eg (aryl) ₂ -CuLi], organotin (eg aryl- If Sn (CH ₃ ) ₃ , aryl-Sn (CH ₂ CH ₂ CH ₂ CH ₃ ) ₃ ] or other organometallic reagents are not commercially available, they can be readily prepared using suitable methods known in the literature.

This type of coupling reaction requires the use of a suitable solvent. Such solvents include, but are not limited to, dioxane, THF, methylene chloride, chloroform, benzene, hexane, ethyl ether, tert-butyl methyl ether, or combinations or mixtures thereof. The coupling reaction may or may not require the presence of a catalytic amount of catalyst. Such catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (0), PdCl ₂ , Pd (OAc) ₂ , (CH ₃ CN) ₂ PdCl ₂ , Pd (dppf) ₂ .

The reaction temperature may vary from -78 ° C to more than 100 ° C, ie in the reflux temperature range of the solvent. Alternatively, this reaction process step can be carried out under suitable microwave irradiation conditions as necessary. This reaction may or may not require a sealed reaction vessel, and the internal pressure may vary in the range of 1 to 100 atmospheres.

Method E is a suitable precursor for the final substituent R ₁ (eg, acidic groups of compounds (4), (5), (9), (11), (15), (16), (17) or (18)). -COOH). Modifications of this type can be made using strategies established in the art. This variant is coupled in one step (eg, with standard amine conditions, eg amine HN (R _{10 ′} ) R _b under EDC / HOBT / ET ₃ N in CH ₃ CN; standard coupling conditions, eg For example, coupling with DCC in DCM, alcohol under DMAP, HOR _b to form esters or reducing with alcohols) or more than one step (e.g., to form isocyanates via Curtuis rearrangement, followed by amines Or the formation of urea using acid chloride formation, followed by addition of an amine, HN (R _{10 ′} ) R _b or an alcohol, HOR _b with a non-nucleophilic base such as DIPEA in DCM. . This conversion may first require a deprotection step to place the precursor (eg, -CO ₂ Me is hydrolyzed to LiOH / THF / water to produce -COOH).

The preparation of compounds of formula (Ia) can also be accomplished via compound (7), which can then be constructed from aldehyde (1) shown in Scheme 2. Suitable conversions in Scheme 2 can be completed using suitable methods from methods A through E.

Method F is for the selective substitution of a suitable aldehyde (1) with an amine (R ₃ -NH ₂ ). This type of substitution can be carried out using triethylamine and the preferred amine R ₃ NH ₂ in chloroform for 10 minutes at room temperature. The reaction was very effective in alkyl amines (78-95% yield). In the case of aryl or heteroaryl amines, elevated temperatures (reflux or microwave irradiation), extended reaction times (overnight or 24 hours) and the presence of NaH (or Na) may be required to complete the reaction. When using 3 equivalents or more of a preferable amine, use of a base can be skipped. Other suitable bases include, but are not limited to, pyridine, diisopropyl ethylamine or pyrrolidine, which are also in suitable organic solvents including THF, diethyl ether, DCM, DMF, DMSO, toluene or dioxane, and the like. Can be used.

Method G is for the cyclization of compound (8) to compound (9). This may lead to compounds (8) being either olefin formers (e.g. Wittig reagent) or amide formers (e.g. acids, chloride acids, esters) or agents having potential reactivity such as bis (2, 2,2-trifluoroethyl)-(methoxycarbonylmethyl) -phosphonate, bis (2,2,2-trifluoroethyl)-(ethoxycarbonylmethyl) phosphonate, bis (2 , 2,2-trifluoroethyl)-(isopropoxycarbonylmethyl) phosphonate, (diethoxy-phosphoryl) -acetic acid methyl ester, (diisopropoxy-phosphoryl) -acetic acid methyl ester, ( Diphenyloxy-phosphoryl) -acetic acid methyl ester, (diethoxy-phosphoryl) -acetic acid ethyl ester, (diisopropoxy-phosphoryl) -acetic acid ethyl ester, (diphenyloxy-phosphoryl) -acetic acid ethyl ester Mixed with acetic acid, thioacetic acid, acetic anhydride, melumic acid, or acetyl chloride And it can be carried out. To complete the reaction, elevated temperature (reflux or microwave irradiation), extended reaction time (overnight or 24 hours) and the presence of triethyl amine, diisopropyl ethyl amine, NaOAc, or NaH (or Na) may be required. The reaction solvent can be DCM, THF, toluene, DMSO or DMF. During the cyclization reaction, the protected group (—CO ₂ Me in compound (9)) may or may not be hydrolyzed. Using output may be advantageous for extended structure-activity-relationship (SAR) studies. If desired, hydrolysis can be achieved by mixing with LiOH in THF / water. Different protecting groups at this location (eg tert-butyl) may require different deprotection methods (eg treatment with TFA).

The preparation of compounds of formula (I) can be accomplished via compound (14), which can then be constructed from aldehyde (1) shown in Scheme 3. Suitable conversions can be completed in Scheme 3 using suitable methods from methods A-G.

Method H is for the reduction of a double bond directly linked to a carbonyl group [—C (═O) —]. This type of conversion can be carried out using suitable methods recorded in the literature for the 1,4-reduction of the Enone system [eg, -CH = CH-C (= 0)-]. Such methods include Li / NH ₃ , H ₂ (catalyst Rh-Al ₂ O ₃ ), NaBH ₄ / CoCl ₂ .6H ₂ O, NaBH ₃ CN / ZnCl ₂ , LiHCu (n-Bu), or Et ₃ SiH. Includes use.

The preparation of compounds of formula (I) can be accomplished via compound (2), which can then be constructed from aldehyde (1) shown in Scheme 4. Suitable conversions in Scheme 4 can be completed using suitable methods from methods A-H.

The preparation of compounds of formula (I) can be achieved via compound (2), which can then be constructed from aldehyde (1) shown in Scheme 5. Suitable conversions in Scheme 5 can be completed using suitable methods from methods A-H.

Compounds of formulas (II) and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI), (VIa) (VIa) (VIi) may be synthesized using the synthetic procedures described in Schemes 1-5 above, except that reagents suitable for methods C and D should be used. Can be obtained by application. Examples of such reagents include, but are not limited to, those shown in Scheme 6. Suitable reagents for the methods C and D used in the preparation of the compounds of formulas VIb to VIi require the presence of G5 to G8 in the appropriate position.

Examples of Reagents Used in Methods C and D for the Preparation of Compounds of Formulas (II) and (IIa)

Examples of Reagents Used in Methods C and D for the Preparation of Compounds of Formulas (III) and (IIIa)

Examples of Reagents Used in Methods C and D for the Preparation of Compounds of Formulas (IV) and (IVa)

Examples of Reagents Used in Methods C and D for the Preparation of Compounds of Formulas (V) and (Va)

Examples of Reagents Used in Methods C and D for the Preparation of Compounds of Formulas (VI) and (VIa)

Starting material (1) (Scheme 7) is a well known literature procedure in which POCl ₃ and DMF are used, such as Santilli et al., J. Heterocycl. Chem. (1971), 445-53, which may be obtained from the commercially available 4,6-dihydroxy-2-methylmercaptopyrimidine.

Intermediate (2) (Scheme 7) is produced by two different routes. In the first route, dichloro aldehyde (1) (Scheme 7) is imine by coupling an aryl amine (Santilli et al., J. Heterocycl. Chem. (1971), 445-53) in the presence of NaH in DMSO. (13) The desired compound (2) (Scheme 7) is obtained together with (Scheme 7). The imine is converted to aldehyde (2) (Scheme 7) by treatment with aqueous HCl in THF. The conversion of compound (1) (Scheme 7) to compound (2) (Scheme 7) can also be carried out using triethylamine and the preferred amine in chloroform for 10 minutes at room temperature. This reaction is very effective in the case of alkyl amines (78-95% yield). For aryl amines, elevated temperature (reflux temperature) and extended reaction time (24 hours) are required to complete the reaction. If more than 3 equivalents of amine are used, the use of base can be omitted. Other suitable bases include, but are not limited to, pyridine, diisopropyl ethylamine or pyrrolidine, which may also be used in suitable organic solvents including THF, diethyl ether or dioxane and the like.

In the second route, nitrile (9) (Scheme 7) is prepared in three steps from aldehyde (1) (Scheme 7) (Santilli et al., J. Heterocycl. Chem. (1971), 445-53 ]). Dichloronitrile (9) (Scheme 7) is coupled with aryl amine in the presence of NaH in DMSO to give the desired compound (10) (Scheme 7). Other suitable bases such as pyridine, diisopropyl ethylamine or sodium can also be used in suitable organic solvents such as THF, DMF or dioxane. The preparation and use of nitrile (9) (Scheme I) can also be found in PCT / US01 / 06688 (March 2, 2001, the disclosure of which is incorporated herein by reference in its entirety). have.

Nitrile (10) (Scheme 7) is readily reduced to DIBAL in dichloromethane at room temperature (Boschelliat et al., J. Med. Chem. (1998), 4365-4377) to give unsubstituted imine (13). (2) (Scheme 7) is obtained together with (R = H). The imine is hydrolyzed in situ with compound (2) (Scheme 7) using HCl. Another reducing agent such as lithium aluminum hydride, Raney Ni or SnCl ₂ is used in a suitable organic solvent such as THF, diethyl ether or dioxane to give compound (10) (Scheme 7) (Scheme 7) Can be converted to

Compound (3) (Scheme 7) by coupling aldehyde (2) (Scheme 7) to arylboronic acid using a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) under Suzuki coupling conditions Obtained in good yield. Alternatively, the non-aryl coupling reaction of compound (2) (Scheme 7) using aryl or heteroaryl organo zinc, organocopper, organotin or other known organometallic reagents, For example, compound (3) (Scheme 7) can be obtained (see, eg, Solberg, J .; Undheim, K. Acta Chemica Scandinavia 1989, 62-68). Substitution of chlorine in compound (2) (Scheme 7) also includes nitrogen nucleophiles (see US Pat. Nos. 3,631,045 and 3,910,913 for related aminations), sulfur nucleophiles (Tumkevicius, S. Liebigs Ann. 1995, 1703-1705) , Oxygen nucleophiles or alkyl nucleophiles.

Compound (3) (Scheme 7) is then converted to pyridopyrimidinone (5) (Scheme 7) by one of three procedures. The first procedure converts compound (3) (Scheme 7) to compound (4) (Scheme 7) using a Wittich reaction modified by Horner-Emmons. In this reaction, aldehyde (3) (Scheme 7) is treated with a suitable phosphide, such as triethyl phosphonoacetate or methyl diethylphosphonoacetate, to obtain olefin intermediate (4) (Scheme 7). The reaction is carried out under reflux in a suitable base such as sodium hydride, sodium methoxide or sodium hydroxide and a suitable organic solvent such as diethyl ether, dioxane or ethanol. Conversion of compound (3) (Scheme 7) to compound (4) (Scheme 7) can also be carried out using a Peterson olefination reaction, or of an aldol-based using acetic anhydride, malonic acid and its monoalkyl ester or ethyl acetate It can be carried out using an olefination reaction.

After heating compound (4) (Scheme 7) to 220 ° C. in toluene in a closed tube (Matyus et al. Heterocycle (1985), 2057-64), the solvent was removed to remove the desired product (5) ( Scheme 7 is obtained. This reaction can be carried out in a suitable organic solvent such as organic hydrocarbon, cresol, dioxane, DMF, pyridine or xylene in the presence of a suitable base such as DBU or diisopropylethyl amine, pyridine, lithium bi (trimethylsilyl) amide or LDA. Can be.

The second procedure involves the Horner-Emons reaction, including Still modifications (Still et al., Tetrahedron Lett. (1983), 4405-8; Jacobsen et al., Tetrahedron (1994), 4323-34). ]) Is used to produce a mixture of the desired product (5) (Scheme 7) and trans isomer (4) (Scheme 7). The trans isomer (4) (Scheme 7) is isolated and heated to 220 ° C. in toluene in a closed tube as described above to convert to the desired product (5) (Scheme 7).

The third procedure involves the acetylation of compound (3) (Scheme 7) followed by an acetylating agent (such as acetic anhydride, acetyl chloride or ketene) and a suitable base (such as pyridine, isopropyl ethylamine or pyrrolidine). Intramolecular aldol condensation, promoted by the compound, from which compound (5) (Scheme 7) is produced in very good yield. The third procedure is most suitable when R ₃ is optionally substituted aryl or heteroaryl. If R ₃ is an arylalkyl or heteroarylalkyl substituent, it is unclear whether the reaction forms an important intermediate of formula (VII) shown below (compound (3a) (Scheme 8), which can optionally be isolated as shown in Scheme 8 below. The compound of formula (VII) is preferably not isolated, but is further reacted with a base or cyclized to compound (5) (Scheme 7) by heat, The first and second procedures for all other R ₃ residues. Should be used.

Oxidation of sulfide (5) (Scheme 7) to sulfone (6) (Scheme 7) can be performed in high yield and purity using meta-chloroperoxybenzoic acid (mCPBA). Oxidation methods suitable for use herein include obtaining sulfoxides or sulfones using one or two equivalents of meta-chloroperoxybenzoic acid (mCPBA) or oxone®. Oxidation of sulfides to sulfoxides or sulfones also results in OsO ₄ and catalytic tertiary amine N-oxides, hydrogen peroxide, other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, potassium persulfate, sodium hypochlorite Can be done by

Substitution of sulfone (6) (Scheme 7) with final product (7) (Scheme 7) is usually carried out with an excess of amine in N-methylpyrrolidine (Barvian et al., J. Med. Chem. (2000), 4606-4616). A wide range of primary amines perform this reaction in good yields. In some cases (for O-substitution or sulfonamide formation), the anion of the nucleophile is prepared using a base in dimethylformamide (usually sodium hydride) and then added to the sulfone. The yield of this reaction is usually lower. Similarly, related sulfones and sulfoxides of the compounds of the invention wherein X is SO-alkyl or SO ₂ -alkyl are reported in the literature to be substituted by a wide variety of nucleophiles. Thus, analogs of the compounds of the invention wherein X is an alkyl sulfone or sulfoxide are preferably without further base catalysis, preferably in polar aprotic solvents (eg N-methyl pyrrolidin-2-one (NMP), etc.). Depending on the degree of nucleophilicity of the amine, it may be substituted by primary and secondary alkylamines at different temperatures. For example, the substitution of the sulfone for the analog of the compound of formula (I) in NMP with ethanolamine occurs within 30 minutes at 65 ° C., with the more masked amines such as tris (hydroxymethyl) -aminomethane elevated and extended. Reaction time (80 ° C., reaction time over 24 hours) may be required. Sulfones are also substituted by primary or secondary amines with additional non-nucleophilic bases (eg, DIPEA) at different temperatures depending on the degree of nucleophilicity of the amine in aprotic solvents such as DCM, CH ₃ CN, NMP Can be.

In addition, sulfones may be substituted with substituted arylamines or heteroarylamines at elevated temperatures, where it is sometimes required to form aryl or heteroarylamines with sodium hydride or other suitable base in DMSO. In addition, the sulfoxide analogs of formula I can be readily substituted with aluminum salts of aryl or heteroaryl amines as already described in patent document (WO 99/32121). Likewise, sulfone and sulfoxide analogs of Formulas (I) and (Ia) may be substituted with aryl or heteroaryl or alkyl thiols, or alkyl or aryl or heteroaryl alcohols. For example, analogs of formula (I) containing sulfone with X substituents may be substituted with sodium alkoxides in alcohols or alternatively a suitable base such as sodium, NaH or sodium bistrimethylsilyl amide in a polar aprotic solvent such as DMSO May be substituted with reactive alkoxides or phenoxide nucleophiles, which may be produced from alcohols or phenols, or proceed with a forward reaction. Similarly, for example, sulfones associated with formulas (I) and (Ia) may be substituted with carbon nucleophiles such as aryl or alkyl Grignard reagents or related organometallics such as organo lithium, zinc, tin, copper or boron. These reactions may in some cases require the action of transition metal catalysts (eg Pd or Ni catalysts). Related 2-pyrimidine sulfones are substituted with cyanide, malonate anions, deactivated enolates, or heterocyclic C nucleophiles such as 1-methylimidazole anions by generation of anions by NaH or other suitable base in THF It is also already known (see, eg, Chem Pharm Bull. 1987, 4972-4976). For example, analogs of compounds of formulas (I) and (Ia) in which X is alkyl sulfone are produced by treating 1-methyl imidazole with n-butyl lithium in a solvent such as THF at a temperature of about -70 ° C. Substitution with an anion of C-alkylated product on imidazole C-2 can be obtained.

For the purposes herein, compounds of Formulas (I), (Ia), (II) and (IIa) wherein X is R ₂ or NHS (O) _m R ₂ are appropriate “X” defined in Formulas (I) and (Ia) from Compound (6) (Scheme 7). It can be obtained by substituting a sulfone with a functional group. In order to obtain compounds of the formulas (I), (la) and (la) in which X is S (O) _m R ₂ and R ₂ is not methyl, the sulfones on the corresponding compound (6) (Scheme 7) are thiol (R ₂ SH) After substitution by, it is optionally oxidized with a suitable oxidizing agent such as MCPBA or KMnO ₄ . Oxidation methods suitable for use herein include obtaining sulfoxides or sulfones using oxidizing agents such as one or two equivalents of meta-chloroperoxybenzoic acid or oxone®. Oxidation of sulfides to sulfones can also be carried out using OsO ₄ and catalytic tertiary amine N-oxides. Other methods used for sulfide oxidation include the use of hydrogen peroxide, other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, potassium persulfate and sodium hypochlorite.

Compound (8) (Scheme 7) can also be prepared by heating trans ester (4) (Scheme 7) in alcohol in the presence of the corresponding sodium alkoxide. The yield of the reaction was very high when using primary alcohol, but longer reaction time was required when using secondary alcohol. Sodium alkoxides can be readily prepared from the corresponding alcohols and bases such as sodium or sodium hydride.

Reduction of trans ester (4) (Scheme 7) with SmI ₂ affords reduced analog (11) (Scheme 7). This reduction can also be carried out using other reducing agents such as hydrogen gas, lithium, magnesium or sodium borohydride in a suitable organic solvent such as THF, ethanol or diethyl ether.

Cyclization of ester (11) (Scheme 7) is carried out with sodium methoxide in methanol to give reduced analog (12) (Scheme 7). Other organic bases such as sodium, sodium ethoxide or TEA can be used in suitable organic solvents such as methanol, ethanol or dioxane. The product 12 (Scheme 7) can also be obtained by heating the ester (11) (Scheme 7) to 150 ° C. in a suitable organic solvent such as toluene, xylene or isopropanol.

Further preparation procedures for intermediates similar to the intermediates in the present invention are known to those skilled in the art from WO 99/41253, US Patent 6,200,977; US 6,153,619; US 6,268,310; US 5,468,751; US 5,474,996 and EP 1 040 831.

Another exemplary preparation of a compound of Formula VII is shown in Scheme 8 below.

The preparation of compounds of Formula (A), (Al), (B) or (B1) can be accomplished from the appropriate intermediates of Schemes 1-5 using suitable synthetic methods described in the literature and known to appropriately trained scientists. Examples of this type of preparation have been demonstrated in Scheme 9 and others. The above preparation is carried out by reacting compound (16) (or a compound of formula A or B) or compound (3) (or a compound of formula A1 or B1) with another reagent having the appropriate structure as shown in Scheme 9 using Method I. Can be done.

Method I is for the substitution of -LG ₂ with a suitable compound containing the structural unit -YH. This can be done by heating the reaction mixture in a suitable solvent. The heating method can be selected from standard oil baths or microwave irradiation. The solvent may be CH ₂ Cl ₂ , DMSO, DMF, toluene, benzene, CH ₃ CN or NMP. The reaction may or may not require the presence of a base. Examples of bases may be selected from, but are not limited to, triethyl amine, diisopropyl ethyl amine, NaH, n-BuLi, tert-BuLi, tert-BuOK, Li ₂ CO ₃ , Cs ₂ CO _3, and pyridine Do not. Such modifications may also require the presence of a catalyst containing a catalytic amount of transition metal (eg, Pd, Cu, Ni or W). Such catalysts include, but are not limited to, Pd / C, Pd (PPh ₃ ) ₄ and PdCl ₂ . Compounds with Y = S (O) _m or S (O) _m C (R _y ) (R _z ) can also be prepared by oxidizing the corresponding compound with Y = S or SC (R _y ) (R _z ). Can be. Suitable oxidation methods for use herein include, but are not limited to, mCPBA, oxone, OsO ₄ , H ₂ O ₂ , potassium and zinc permanganate.

Another aspect of the invention is the novel intermediate of formula (X).

Where

R ₁ is a substituted aryl ring as defined herein for compounds of Formulas I and II;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl Reel C _{1 - 10} alkyl residue (these residues are optionally substituted), and;

R _{12 'is} C _{1 - 10} alkyl, aryl, heteroaryl or aryl alkyl;

m is 0 or an integer having a value of 1 or 2;

R _g is C _{1 - 4} is alkyl.

Preferably, R _g is C _{1 - 4} alkyl and, more preferably, methyl.

Preferably, m is 0 or an integer having a value of 1 or 2. More preferably, m is 0 or 2.

Another aspect of the invention is the novel intermediate of formula (XI).

Where

R ₃ , R _{12 '} , m and R _g are as defined for Formula VII above;

R ₁ is a substituted ring as defined in the compound of formula III.

Another aspect of the invention is the novel intermediate of formula (XII).

Where

R ₃ , R _{12 '} , m and R _g are as defined for Formula VII above;

R ₁ is a substituted ring as defined in the compound of formula IV.

Another aspect of the invention is the novel intermediate of formula (XIII).

Where

R ₃ , R _{12 '} , m and R _g are as defined for Formula VII above;

R ₁ is a substituted ring as defined in the compound of formula V.

Another aspect of the invention is the novel intermediate of formula XIV.

Where

R ₃ , R _{12 '} , m and R _g are as defined for Formula VII above;

R ₁ is a substituted ring as defined in the compound of formula VI.

Another aspect of the invention is the novel intermediate of formula XV.

Where

R ₁ is a substituted phenyl ring as defined in Formula I or II;

R ₃ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl residue (these residues are optionally substituted), and R ₃ is not a single R ₁ is chlorine in the case of hydrogen;

m is 0 or an integer having a value of 1 or 2;

R _g is C _{1 - 4} is alkyl.

In one embodiment, R ₃ is optionally substituted C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl alkyl, alkyl or aryl.

In other embodiments, any of the R ₃ substituents is independently selected from halogen, alkyl, hydroxy, alkoxy, amino or halo-substituted alkyl.

Another aspect of the invention is the novel intermediate of formula XVI.

Where

R ₁ is as defined for the compound of Formula I or II;

R ₃ , R _g and m are optionally substituted aryl or heteroaryl residues as defined for the compound of formula VII.

Another aspect of the invention is the novel intermediate of formula XVII.

Where

R ₁ is as defined for the compound of Formula III or VI;

R ₃ , R _g and m are optionally substituted aryl or heteroaryl residues as defined for the compound of formula VII.

Another aspect of the invention is a compound of Formulas C and C1.

Where

G1, G2, G3 and G4 are as described for Formulas I and Ia herein;

m is 0 or an integer having a value of 1 or 2;

R _g is C _{1 - 10} alkyl;

LG ₂ is chlorine, bromine, iodine or OS (O) ₂ CF ₃ ;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} alkyl moiety is the (each of these moieties may optionally be substituted, as defined for formula (I) and (Ia) herein).

In one embodiment, R _g is methyl. In another embodiment, m is 0 or 1.

Another aspect of the invention is a compound of D and D1 having the structure shown below.

Where

G1, G2, G3, G4 and X are as described herein for the compounds of Formulas I and Ia;

LG ₂ is chlorine, bromine, iodine or OS (O) ₂ CF ₃ ;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} alkyl moiety is the (each of these moieties may optionally be substituted, as defined for formula (I) and (Ia) herein).

Another aspect of the invention is a compound of E and E1 having the structure shown below.

Where

G1, G2, G3, G4, R ₁ and (R ₁ ) _g are as described herein for the compounds of Formulas I and Ia;

m is 0 or an integer having a value of 1 or 2;

R _g is C _{1 - 10} alkyl;

LG ₂ is chlorine, bromine, iodine or OS (O) ₂ CF ₃ ;

R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} alkyl moiety is the (each of these moieties may optionally be substituted, as defined for formula (I) and (Ia) herein).

It is also recognized that similar sets of Formulas F and F1 are contemplated when the R ₁ residue is substituted at the 3-position of the phenyl ring as shown in compounds of Formulas II and IIa. Similar intermediates are also contemplated for the rest of the compounds herein where the C4 position of the pharmacological action, for example G5 / G6 of the formula described herein as Formulas III and IIIa, IV and IVa, etc. is substituted with various heteroaryl rings. .

Another aspect of the invention is a compound of formula XVIII.

Where

R ₁ , R _{1 ′} , g and R ₃ are as defined for Formula I herein.

Another aspect of the invention is a compound of formula XIX.

Where

R ₁ , R _{1 ′} , g and R ₃ are as defined for Formula II herein.

Synthetic Example

The invention will now be described with reference to the following examples, which are for illustrative purposes only and are not intended to limit the scope of the invention. All temperatures are in degrees Celsius, all solvents have the highest available purity, and all reactions are performed under dry conditions under argon atmosphere as needed.

List of abbreviations

EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride dppf: 1,1'-bis (diphenylphosphino) ferrocene DMAP: 4- (dimethylamino) pyridine DMSO: dimethyl sulfoxide m-CPBA: 3-chlorobenzene-carboperoxoic acid EtOAc: ethyl acetate HPLC: High Pressure Liquid Chromatography DIPEA or DIEA: N, N-diisopropylethylamine DCM: Dichloromethane SPE: Solid Phase Extraction TFA: trifluoroacetic anhydride MDAP: Mass-induced Automated Manufacturing HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate HBTU: O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate NIS: N-iodosuccinimide HOBT: 1-hydroxybenzotriazole hydrate DMF: N, N-dimethylformamide THF: tetrahydrofuran IPA: Isopropyl Alcohol M: molarity DSC: Differential Scanning Calorimeter mmol: mmol mL: milliliters aq: aqueous mg: mg eq: equivalent rt: room temperature mp: melting point min: min g: grams L: liter h: hour mol: mol satd: saturated NMP = 1-methyl-2-pyrrolidinone mEq: milliequivalents

Other abbreviations used herein are described in the ACS Style Guide (American Chemical Society, Washington, DC, 1986), the disclosure of which is incorporated herein by reference in its name.

LC-MS Experimental Conditions:

Liquid chromatography

System: Shimadzu LC System with SCL-10A Controller and Dual UV Detectors

Autosampler: Leap CTC-Valco 6 port injector

Column: Aquasil / Aquasil (C18 40 × 1 mm)

Injection volume. (Μl): 2.0

Solvent A: H ₂ O, 0.02% TFA

Solvent B: MeCN, 0.018% TFA

Gradient: linear

Channel A: UV 214 nm

Channel B: ELS

Mass Spectrometer: PE Sciex Single Quadrupole LC / MS API-150

Polarity: positive

Detection mode: profile

General procedure

Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AC 400 spectrometer. CDCl ₃ is deuterium chloroform, DMSO-d ₆ is hexadeuterium dimethylsulfoxide and CD ₃ OD (or MeOD) is tetradeuterium methanol. Chemical shifts were recorded in downfield (δ), 10 ⁻⁶ units, from internal standard tetramethylsilane (TMS) or NMR solvent. Abbreviations for NMR data are as follows: s = single peak, d = double peak, t = triple peak, q = quadruple peak, m = multiple peak, dd = double peak of double peak, dt = double peak of double peak Peak, app = apparent peak, br = broad peak. J represents the NMR coupling constant (measured in Hertz). Mass spectra were collected on the instrument using electrospray (ES) ionization techniques. All temperatures are reported in degrees Celsius (° C.).

Analtech Silica Gel GF and E. Thin layer chromatography was performed using an E. Merck silica gel 60 F-254 thin layer plate. Doing both flash and gravity chromatography. It was performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Gilson using a Luna 5u C18 (2) 100A reversed phase column eluting with 10-80 gradient (0.1% TFA / 0.1% aqueous TFA in acetonitrile) or 10-80 gradient (acetonitrile / water) Preparative HPLC was performed using a preparative system. The CombiFlash system used for purification in this application was purchased from Isco, Inc. Combiflash purification was performed using a prepacked SiO ₂ column, a detector using a UV wavelength of 254 nm, and a mixed solvent.

Heating of the reaction mixture by microwave irradiation was purchased from Smith Creator (Personal Chemistry, Porboro, Mass., USA, now owned by Biotage), Emrys Optimizer ( Either from Personal Chemistry) or Explorer (CEM Discover, Matthews, North Carolina).

General Procedure for EDC Coupling

The acid was dissolved in CHCl ₃ and EDC (1.1 equiv; hereinafter “eq.”) Was added. Amine (2 equiv) was added dropwise followed by DMAP (approx. 2 equiv) dropwise and stirred until the reaction was judged complete. The reaction mixture was washed with water. The aqueous portion was extracted with ethyl acetate. The ethyl acetate portion was washed with brine, combined with the other organic portion, dried (MgSO ₄ ) and concentrated.

General procedure for sulfide oxidation

Sulphide was dissolved in CHCl ₃ and mCPBA (1.5 equiv) was added. The mixture was stirred for 30 minutes (hereinafter “min”) and then quenched with NaHCO ₃ . The organic portion was washed with brine and dried (MgSO ₄ ).

General procedure for sulfoxide / sulfone substitution

Sulfoxide / Sulfone was dissolved in THF and amine (5 equiv) was added and stirred for 1 hour. The mixture was concentrated in vacuo.

Example 1

N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide

1a) 4-chloro-8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one

To a solution of oxychloride phosphorus (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly while maintaining a temperature of 5 ° C to 10 ° C. Subsequently, the solution was allowed to warm to room temperature and then 6-hydroxy-2- (methylthio) -4 (1H) -pyrimidinone (25 g, 0.16 mol) was added in portions. The resulting reaction mixture was heated at 80 ° C. overnight then concentrated in vacuo. The resulting slurry, like residue, was poured onto ice, stirred for 2 hours and then filtered to afford the crude product. The crude product was further purified by recrystallization with hexanes to give 4,6-dichloro-2- (methylthio) -5-pyrimidinecarbaldehyde (21.3 g, 61%).

2,6-difluoroaniline (5.35 mL, 49.3 mmol) in a solution of 4,6-dichloro-2- (methylthio) -5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) , 1.1 equiv) followed by Et ₃ N (12.6 mL, 89.6 mmol, 2 equiv). The reaction mixture was heated to 55 ° C. for about 22 hours and then concentrated. The slurry was again dissolved in DCM (250 mL), washed with H ₂ O (2 × 100 mL), then concentrated and further washed with acetone (2 × 10 mL) to give pure 4-chloro-6-[(2 , 6-difluorophenyl) amino] -2- (methylthio) -5-pyrimidinecarbaldehyde was obtained 9.87 g (70%). LC-MS mlz 316 (M + H) ⁺ .

4-chloro-6-[(2,6-difluorophenyl) amino] -2- (methylthio) -5-pyrimidinecarbaldehyde (200 mg in DMF (4.0 mL) and acetic anhydride (2.0 mL) , 0.63 mmol) was heated with microwave (160 ° C.) for about 30 minutes. The resulting mixture was then concentrated. Flash chromatography (EtOAc / hexanes, 1: 5) was carried out to give the title compound (109 mg, 51%). LC-MS mlz 340 (M + H) ⁺ .

1b) 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -4-methylbenzoic acid

4,4,4 ', 4', 5,5,5 'in a stirred solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1 equiv) in degassed DMF (1400 mL, 23.3 vol) Potassium acetate (112 g, 1.14 mole, 5 equiv) after charging, 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (81.4 g, 0.32 mol, 1.4 equiv) And [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) (18.7 g, 0.02 mole, 0.1 equiv). The resulting mixture was placed under a nitrogen atmosphere and heated at 80 ° C. in the dark overnight. The mixture was then concentrated under high vacuum and the residue was partitioned between EtOAc and 2M HCl. The mixture was then filtered and the layers separated. The aqueous phase was extracted again with EtOAc. The combined organics were then washed with brine, dried and evaporated to afford a brown solid, which was eluted with 2: 1 cyclohexane: ethyl acetate after it was applied to a silica plug. The fractions were then combined and evaporated to give a brown foam which was triturated with cyclohexane, collected by filtration and dried under vacuum to afford 4-methyl-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzoic acid was obtained.

4-chloro-8- (2,6-difluorophenyl) -2- (methyl) in DME (150 mL) and H ₂ O (50 mL) in pressure flask (500 mL, Chemglass) In a solution of thio) pyrido [2,3-d] pyrimidin-7 (8H) -one (1.70 g, 5.00 mmol) 4-methyl-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzoic acid (1.97 g, 7.50 mmol) and K ₂ CO ₃ (4.15 g, 30.0 mmol) were added. The resulting mixture was degassed with argon for 5 minutes, mixed with Pd (PPh ₃ ) ₄ (0.232 g, 0.20 mmol) and heated for 30 minutes with vigorous stirring in a preheated oil bath (160 ° C.). The reaction mixture was filtered through celite and concentrated in vacuo to remove DME. Then it was combined with EtOAc (200 mL) and AcOH (2.5 mL) and shaken. The layers were separated. The organic layer was collected, further washed with brine (70 mL), dried over Na ₂ S0 ₄ , filtered, concentrated and via flash chromatography (load column using DCM, mobile phase EtOAc / hexanes) Purification gave 2.15 g (98%) of the title compound as a white solid.

1c) N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d in CH ₂ Cl ₂ (10.0 ml) ] In a solution of pyrimidin-4-yl] -4-methylbenzoic acid (246.0 mg, 0.5 mmol), DMAP (122.0 mg, 1.0 mmol), EDC (115.0 mg, 0.6 mmol), HOBT (81.0 mg, 0.6 mmol) and 1-cyclopropylmethanamine (71.0 mg, 1.0 mmol) was added. The reaction mixture was stirred at rt for about 14 h and concentrated. Then diluted with H ₂ O (5.0 mL) and EtOAc (10.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Then, the mixture was purified through a combiflash system (hexane: ethyl acetate = 3: 1) to give N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (methylthio)- 7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide (210.0 mg, 85%) was obtained. LC-MS mlz 493 (M + H) ⁺ , 2.33 min (ret. Time).

N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydro in CH ₂ Cl ₂ (15.0 mL) To a solution of pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide (493.0 mg, 1.0 mmol) was added m-CPBA (449.0 mg, 2.0 mmol). The reaction mixture was stirred at rt for about 12 h and concentrated. It was diluted with H ₂ O (5.0 mL) and EtOAc (20.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Purification via combiflash system (hexane: EtOAc = 4: 1) gave the title sulfone compound (490.0 mg, 93%). LC-MS mlz 526 (M + H) ⁺ , 2.00 min (ret. Time).

1d) N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide

N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-di in THF (5.0 milliliters (hereinafter “mL”)) 2-amino-3 in a solution of hydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide (50.0 mg ("mg"), 0.095 mmol ("mmol")) Propanediol (10.0 mg, 0.105 mmol, 1.1 equiv) was added. The reaction mixture was stirred at rt for about 4 h (" h &quot;) and concentrated. Then purification via combiflash system (DCM: MeOH = 1: 10) afforded the title compound. LC-MS mlz 536 (M + H) ⁺ , 1.70 min (ret. Time).

Example 2

N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl] -4-methylbenzamide

2a) 1,1-dimethylethyl 4-{[4- (5-{[(cyclopropylmethyl) amino] carbonyl} -2- (methylphenyl) -8- (2,6-difluorophenyl) -7 -Oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -1-piperidinecarboxylate

The title compound was converted to N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl) -4-methylbenzamide and 1,1-dimethyl ethyl 4-amino-1-piperidinecarboxylate according to the procedure of Example 1d.

2b) N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -4-methylbenzamide

1,1-dimethylethyl 4-{[4- (5-{[(cyclopropylmethyl) -amino] carbonyl} -2-methylphenyl) -8- (2,6-difluoro in THF (2 mL) TFA (3.0 mL) is added to a solution of phenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} -1-piperidinecarboxylate It was. The reaction mixture was stirred for about 12 hours and concentrated. The residue was mixed with H ₂ O (5.0 mL) and EtOAc (20.0 mL) and the resulting mixture was basified with a 2.5N NaOH aqueous (hereinafter “aq.”) Solution. The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (DCM: MeOH = 10: 1) afforded the title compound. LC-MS mlz 545 (M + H) ⁺ , 1.65 min (ret. Time).

Example 3

N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino ] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

The title compound was converted to N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl) -4-methylbenzamide and 2,2,6,6-tetramethyl-4-piperidinamine were prepared as described in Example 1d. LC-MS mlz 601 (M + H) ⁺ , 1.75 min (ret. Time)

Example 4

N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6.6-tetramethyl-4-piperidinyl) amino]- 7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

The title compound was converted to N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl) -4-methylbenzamide and N-methyl-1,2-ethanediamine as prepared in Example 1d. LC-MS mlz 519 (M + H) ⁺ , 1.60 min (ret. Time).

Example 5

N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-di Hydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

The title compound was converted to N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl) -4-methylbenzamide and (1H-imidazol-2-ylmethyl) amine dihydrochloride as prepared in Example 1d. LC-MS mlz 542 (M + H) ⁺ , 1.61 min (ret. Time).

Example 6

3- [2-[(2-aminoethyl) (methyl) amino] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -N- (cyclopropylmethyl) -4-methylbenzamide

The title compound was converted to N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-methyl sulfone-7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl) -4-methylbenzamide and 1,1-dimethylethyl [2- (methylamino) ethyl] carbamate as prepared in Example 2. LC-MS mlz 519 (M + H) ⁺ , 1.62 min (ret. Time).

Example 7

N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide

7a) 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidine-7 (8H)- On

To a solution of 3-iodo-4-methylaniline (110.0 mg, 0.47 mmol) in dioxane (1.0 mL) (under argon) triethylamine (0.26 mL, 1.86 mmol), palladium diacetate (5.2 mg, 0.023 mmol) ), 2- (dicycloprophexyl phosphino) biphenyl (33.0 mg, 0.093 mmol) and pinacolborane (0.20 mL, 1.40 mmol) were added. The mixture is stirred at about 80 ° C. for about 1 hour, cooled to room temperature (rt), water (0.2 mL), barium hydroxide octahydrate (440.0 mg, 1.40 mmol) and 4-chloro-8- (2,6- Difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one (180.0 mg, 0.47 mmol) was added. The mixture was heated for about 1 hour with stirring at about 100 ° C., cooled to room temperature, filtered through celite and diluted with brine (5.0 mL). The mixture was then extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via the combiflash system afforded the title compound (155.0 mg, 75%). LC-MS mlz 411 (M + H) ⁺ , 2.60 min (ret. Time).

7b) N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 4-yl] -4-methylphenyl} -2-thiophenecarboxamide

4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3- in CH ₂ Cl ₂ (10 mL) at 0 ° C. d] Et ₃ N (200.0 mg, 2.0 mmol, 2.0 equiv), DMAP (5.0 mg, 0.2 mmol, 0.2 equiv) and 2-T in a solution of pyrimidin-7 (8H) -one (411.0 mg, 1.0 mmol) Offencarbonyl chloride (292.0 mg, 2.0 mmol, 2.0 equiv) was added. After addition, the reaction mixture was stirred at room temperature for about 14 hours. The mixture was concentrated and mixed with H ₂ O (5.0 mL) and EtOAc (20.0 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (hexane: EtOAc, 4: 1) afforded the title compound. LC-MS mlz 521 (M + H) ⁺ , 2.57 min (ret. Time).

7c) N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -4-yl] -4-methylphenyl} -2-thiophenecarboxamide

N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2, in CH ₂ Cl ₂ (15.0 mL) M-CPBA (449.0 mg, 2.0 mmol, 2.0 equiv) was added to a solution of 3-d] pyrimidin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide (521.0 mg, 1.0 mmol). . The reaction mixture was stirred at rt for about 14 h, concentrated and mixed with H ₂ O (5.0 mL) and EtOAc (20.0 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (hexane: EtOAc, 4: 1) afforded the title compound. LC-MS mlz 553 (M + H) ⁺ , 2.30 min (ret. Time).

7d) N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate were prepared as described in Example 2. LC-MS mlz 573 (M + H) ⁺ , 1.90 min (ret. Time).

Example 8

N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide and 1,1-dimethylethyl 4-piperidinylcarbamate were prepared as described in Example 2. LC-MS mlz 573 (M + H) ⁺ , 1.90 min (ret. Time).

Example 9

N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -2-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine were prepared as described in Example 1d. LC-MS mlz 629 (M + H) ⁺ , 2.0 min (ret. Time).

Example 10

N- (3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl} -4-methylphenyl) -2-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide and (1H-imidazol-2-ylmethyl) amine dihydrochloride were prepared as described in Example 1d. LC-MS mlz 570 (M + H) ⁺ , 1.70 min (ret. Time).

Example 11

N- [3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl) -methylphenyl] -2-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide and 1,1-dimethylethyl (2-aminoethyl) methylcarbamate were prepared as described in Example 2. LC-MS mlz 547 (M + H) ⁺ , 1.80 min (ret. Time).

Example 12

N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide

12a) N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide

The title compound was purified by 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidine-7 (8H) Prepared as described in Example 7b from -one and 4-fluoro-3-methylbenzoyl chloride. LC-MS mlz 547 (M + H) ⁺ , 2.70 min (ret. Time).

12b) N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide

The title compound is converted to N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide and m-CPBA as prepared in Example 7c. LC-MS mlz 580 (M + H) ⁺ , 2.40 min (ret. Time).

12c) N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate prepared as described in Example 2 It was. LC-MS mlz 599 (M + H) ⁺ , 1.98 min (ret. Time).

Example 13

N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenylN) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-piperidinylcarbamate were prepared as described in Example 2. LC-MS mlz 599 (M + H) ⁺ , 1.99 min (ret. Time).

Example 14

6-chloro-N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide

14a) 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide

The title compound was purified by 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidine-7 (8H) Prepared from -one and 6-chloro-3-pyridinecarbonyl chloride as described in Example 7b. LC-MS mlz 550 (M + H) ⁺ , 2.63 min (ret. Time).

14b) 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide

The title compound was converted to 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -3-pyrimidinecarboxamide and m-CPBA prepared as described in Example 7c. LC-MS mlz 582 (M + H) ⁺ , 2.30 min (ret. Time).

14c) 6-chloro-N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide

The title compound was purified by 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide and prepared as described in Example 2 from 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate It was. LC-MS mlz 602 (M + H) ⁺ , 1.75 min (ret. Time).

Example 15

N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -6-chloro-3-pyridinecarboxamide

The title compound was purified by 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide and 1,1-dimethylethyl 4-piperidinylcarbamate as prepared in Example 2. LC-MS mlz 602 (M + H) ⁺ , 1.75 min (ret. Time).

Example 16

6-chloro-N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-pyridinecarboxamide

The title compound was purified by 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine prepared as described in Example 1d. . LC-MS mlz 658 (M + H) ⁺ , 1.92 min (ret. Time).

Example 17

6-chloro-N- (3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-pyridinecarboxamide

The title compound was purified by 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide and (1H-imidazol-2-ylmethyl) amine dihydrochloride were prepared as described in Example 1d. LC-MS mlz 599 (M + H) ⁺ , 1.92 min (ret. Time).

Example 18

N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -5-fluoro-4-methylbenzamide

18a) 3-fluoro-5-iodo-4-methylbenzoic acid

Benzoic acid (1.54 g, 0.01 mol) was dissolved in trifluoromethanesulfonic acid (10 mL) and cooled to about 0 ° C. NIS (2.25 g. 0.01 mol) was added in portions over 6 hours while maintaining the reaction temperature at about 0 ° C. The mixture was allowed to warm to rt overnight. The reaction mixture was then poured onto ice and extracted with ethyl acetate (3 ×). The organic layer was washed (Na ₂ S ₂ O ₅ ) and concentrated. This material was used as crude material.

18b) N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide

The crude acid (Example 1.5 g) from Example 18a was dissolved in thionyl chloride (75 mL) and heated to 80 ° C. for about 2 hours. The mixture was then cooled to rt and stirred overnight under N ₂ . The mixture was concentrated in vacuo and dissolved in 15 mL of DCM. Na ₂ CO ₃ (3 g) was added together with cyclopropyl amine (0.69 mL, 0.01 mol (hereinafter “mol”)). The mixture was stirred overnight and purified via flash chromatography (5% MeOH / CH ₂ Cl ₂ ) to afford 0.904 g of the title compound.

18c) N-cyclopropyl-3-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

The iodo compound (0.904 g, 2.83 mmol) from Example 18b was dissolved in DMF (30 mL). Bis-Pinikalato-diborane (1.44 g, 2.83 mmol) was added followed by PdCl ₂ .dppf (55 mg) and potassium acetate (1.38 g, 14.15 mmol). The mixture was stirred for about 18 hours, concentrated in vacuo and purified via flash chromatography to afford the title compound (60 mg).

18d) 4-chloro-8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrimidine -7 (8H) -on

4-chloro-8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one (2.7 mL) in dichloromethane (50 mL) m-CPBA (0.63 g, 4.0 mmol) was added to the solution. The resulting mixture was stirred at rt for 10 min and then concentrated in vacuo. 4-Chloro-2-methylsulfinyl-8- (2,6-difluoro-phenyl) -8H-pyrido [2,3-d] pyri via flash chromatography (EtOAc / hexane, 1: 3) Midin-7-one (88%) was obtained. LC-MS m / z 356 (by solvent electrolysis with methanol, (M + H) ⁺ ).

4-Chloro-2-methylsulfinyl-8- (2,6-difluoro-phenyl) -8H-pyrido [2,3-d] pyrimidin-7-one (0.75 in dichloromethane (30 mL) mmol) was mixed with a solution of cerinol (0.075 g, 0.82 mmol) and Et ₃ N (0.21 mL, 1.5 mmol) in DMF (0.75 mL). The resulting mixture was stirred at rt for about 1 h and then concentrated in vacuo. Through flash chromatography (EtOAc: hexane, 3: 1) the title compound 4-chloro-8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxy-methyl) Ethyl] amino} pyrido [2,3-d] pyrimidin-7 (8H) -one (42%) was obtained.

18e) N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -5-fluoro-4-methylbenzamide

Chloride (0.056 g, 0.17 mmol), borate ester (0.065 g, 0.17 mmol), K ₂ CO ₃ (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05 equiv) in dioxane / water (3: 1, 10 mL) and heated to about 100 ° C. for about 3 hours. The mixture was concentrated and purified via reverse phase HPLC to give the title compound (9 mg, yellow powder, melting point 214.2 to 217.5 ° C.). LC-MS mlz 540 (M + H) ⁺ , 1.69 min (ret. Time). Purity shown by HPLC was 96%.

Example 19

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide

19a) 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared from general] -4-methylbenzoic acid and 4-fluoroaniline according to the general procedure for EDC coupling described in the general experimental paragraph above. The crude reaction mixture was purified via flash chromatography (EtOAc: hexane, 2: 1) to afford the title compound (0.125 g, 34%).

19b) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- General] -N- (4-fluorophenyl) -4-methylbenzamide

The title compound (0.105 g, 79%) was prepared following the general procedure for sulfide oxidation described above.

19c) 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyri [2,3-d] pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was prepared following the general procedure for sulfoxide / sulfone / sulfone substitutions described above. The concentrated reaction mixture was purified via reverse phase HPLC to give the desired compound (43 mg, 39%) as a white solid. LC-MS mlz 576 (M + H) ⁺ , 1.89 min (ret. Time). Purity shown by HPLC (254 nm) was 90%.

Example 20

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide

The title compound was prepared following the procedure described in Example 19 using 2-phenylethanamine in the amide formation reaction. LC-MS mlz 586 (M + H) ⁺ , 1.82 min (ret. Time).

Example 21

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylpropyl) benzamide

21a) N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylbenzamide

Borate ester (0.683 g, 2.27 mmol), chloride (0.768 g, 2.27 mmol), K ₂ CO ₃ (0.941 g, 6.81 mmol) and tetrakistriphenylphosphine palladium (131 mg, 0.11 mmol) in dioxane / water (3: 1) and heated at reflux for about 4 hours. The reaction mixture was then poured into ethyl acetate, washed with water and brine and dried over Na ₂ SO ₄ . The concentrated mixture was purified via flash chromatography to give the desired product (0.6 g, 55%).

21b) N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -4-methylbenzamide

The title compound was prepared following the general procedure for sulfide oxidation described above. It was concentrated to give the desired product (0.3 g, 49%) as a yellow powder.

21c) 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylpropyl) benzamide

The title compound was prepared following the general procedure for sulfoxide / sulfone / sulfone substitutions described above. The concentrated reaction mixture was precipitated with DMSO / water and filtered. The desired product (55 mg, 45%) was obtained as a white solid. Mp 326.3-327.9 ° C., purity 95% by HPLC, LC-MS m / z 587 (M + H) ⁺ , 1.74 min (ret. Time).

Example 22

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N-cyclopropyl-4-methylbenzamide

The title compound is compound N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylbenzamide and 4-piperidinamine prepared according to the general procedure for sulfoxide / sulphone / sulphone substitutions described above. The concentrated reaction mixture was precipitated with ethyl acetate / hexanes and filtered. The desired product (75 mg, 100%) was obtained as a yellow solid. Purity 94% by HPLC, LC-MS mlz 531 (M + H) ⁺ , 1.65 min (ret. Time).

Example 23

N-cyclopropyl-3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine 4-yl] -4-methylbenzamide (0.1 g, 0.2 mmol) is dissolved in DMF (10 mL), (1H-imidazol-2-ylmethyl) amine dihydrochloride (0.053 g, 0.4 mmol) After addition triethylamine (0.167 mL, 1.2 mmol) was added. The mixture was heated to about 60 ° C for about 3 hours. The completion of the reaction was judged by LCMS and the crude mixture was purified via reverse phase HPLC. The purity indicated by HPLC (254 nm) was 95% and the desired product (54 mg, 50%) was obtained as a white powder. LC-MS mlz 528 (M + H) ⁺ , 1.45 min (ret. Time).

Example 24

N-cyclopropyl-3- (8- (2,6-difluorophenyl) -7-oxo-2-{[2- (propylamino) ethyl] amino} -7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl) -4-methylbenzamide

The title compound was converted to N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylbenzamide and N-propyl-1,2-ethanediamine according to the general procedure for sulfoxide / sulfone substitution described above. The concentrated reaction mixture was purified via reverse phase HPLC. The desired product (65 mg, 61%) was obtained as a yellow solid. Melting point 120-134 ° C., purity greater than 95% by HPLC, LC-MS m / z 533 (M + H) ⁺ , 1.84 min (ret. Time).

Example 25

3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (1-methylpropyl) benzamide

The title compound was converted to N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylbenzamide and N, N'-dimethyl-1,2-ethanediamine compound were prepared following the general procedure for sulfoxide / sulfone substitutions described above. The concentrated reaction mixture was purified via reverse phase HPLC. The desired product (69 mg, 67%) was obtained as an off white solid. Mp 214.7-217.5 ° C., purity greater than 95% by HPLC, LC-MS m / z 519 (M + H) ⁺ , 1.54 min (ret. Time).

Example 26

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -N- [2- (4-fluorophenyl) ethyl] -4-methylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- 2- (4-fluorophenyl) ethanamine is used for the amide formation reaction from the acid from the mono] -4-methylbenzoic acid, and 2,2,6,6-tetramethyl-4-piperidineamine is used for the substitution reaction. Prepared according to the procedure of Example 19. LC-MS mlz 669 (M + H) ⁺ , 2.03 min (ret. Time).

Example 27

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N- (cyclopropylmethyl) -4-methylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using (cyclopropylmethyl) amine in the amide formation reaction from the mono] -4-methylbenzoic acid and 4-piperidineamine in the substitution reaction. LC-MS mlz 545 (M + H) ⁺ , 1.63 min (ret. Time).

Example 28

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (2-phenylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- In accordance with the procedure of Example 19 using 2-phenylethanamine in the amide formation reaction from 4-methylbenzoic acid and 2,2,6,6-tetramethyl-4-piperidinamine in the substitution reaction. Prepared. LC-MS mlz 651 (M + H) ⁺ , 1.87 min (ret. Time).

Example 29

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-phenylethanamine in the amide formation reaction from yl] -4-methylbenzoic acid and (2-aminoethyl) methylamine in the substitution reaction. LC-MS mlz 569 (M + H) ⁺ , 1.69 min (ret. Time).

Example 30

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (2-phenylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-phenylethanamine in the amide formation reaction from yl] -4-methylbenzoic acid and (1H-imidazol-2-ylmethyl) amine dihydrochloride in the substitution reaction. . LC-MS mlz 592 (M + H) ⁺ , 1.77 min (ret. Time).

Example 31

N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide

31a) N- (3-iodo-4-methylphenyl) -3-thiophenecarboxamide

3-thiophenecarboxylic acid (2.0 g, 15.6 mmol) was dissolved in methylene chloride (100 mL) and 2 drops of DMF were added. The mixture was cooled to about 0 ° C and oxalyl chloride (1.5 mL, 17.1 mmol) was added slowly and warmed to room temperature. Bubble generation was observed during warming. 3-methyl-4-iodoaniline (5.45 g, 23.5 mmol), 4 drops of pyridine and K ₂ CO ₃ (2.58 g, 18.7 mmol) are dissolved in CH ₂ Cl ₂ (10 mL) and cooled to about 0 ° C. I was. After about 1 hour, the chloride acid mixture was slowly added to the cooled aniline mixture, warmed to room temperature and stirred for about 18 hours. The resulting mixture was filtered, washed with ethyl acetate and the filtrate was concentrated to brown oil. The crude material was purified via flash chromatography (10-30% ethyl acetate in hexanes) to afford the desired product (1.56 g, 29%) as an off-white solid.

31b) N- [4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -3-thiophenecarboxamide

Iodide (1.56 g, 4,5 mmol), bis (pinacolato) diborane (2.3 g, 9.0 mmol), potassium acetate (2.21 g, 22.5 mmol) and PdCl ₂ .dppf (0.15 from Example 31a) g, 0.225 mmol) was dissolved in DMF (50 mL) and heated to about 85 ° C for about 24 hours. The mixture was then concentrated to oil and ethyl acetate and water were added. The organic portion was washed with brine and dried (Na ₂ SO ₄ ). The concentrated organic layer was purified via flash chromatography to give the desired product (0.212 g, 13%).

31c) N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 4-yl] -4-methylphenyl} -3-thiophenecarboxamide

The title compound was prepared according to the procedure of Example 1b from the compound from Example 31b. Flash chromatography was followed by recrystallization (ethyl acetate) to afford the desired compound (0.292 g, 90%).

31d) N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -4-yl] -4-methylphenyl} -3-thiophenecarboxamide

The title compound was prepared according to the general procedure for sulfide oxidation from the compound from Example 31c. The desired compound (0.08 g, 63%; no purification required) was obtained.

31e) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. From the general procedure for sulfoxide / sulfone substitution described above from midin-4-yl] -4-methylphenyl} -3-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine. Prepared accordingly. The concentrated reaction mixture was slurried with acetonitrile and filtered. The solid was recrystallized from methanol / water to give the desired product (0.2 g, 16%) as a crystalline solid. Purity indicated by HPLC was greater than 99%. LC-MS mlz 629 (M + H) ⁺ , 1.86 min (ret. Time).

31f) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide hydrochloride

IPA (5 mL) was added N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) Add to amino] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide (196.5 mg) and at about 60 ° C. Heated. Hydrochloric acid (1.1 equiv; 1 M in water) gave the solution almost clear. Crystallization had already started after a few minutes at about 60 ° C., which was then cooled to room temperature. After stirring for about 3 hours at room temperature, it was filtered, washed with IPA and dried to give the title compound (160.9 mg).

31 g) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide 4-methylbenzenesulfonate

IPA (5 mL) was added N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) Add to amino] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide (203.2 mg) and heated to 60 ° C It was. The solution became clear when p-toluenesulfonic acid (1.1 equiv; 1 M in water) was added. After a few minutes at about 60 ° C it was cooled to room temperature. After stirring for about 3 hours at room temperature, it was filtered, washed with IPA and dried in a vacuum oven at 50 ° C. to give the title compound (123.9 mg). Melting point (tested by DSC) was 335 ° C.

31h) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide methanesulfonate

320 μl of CH ₃ CN was added with N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) Amino] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide (16.0 mg) and at about 60 ° C. Heated. The addition of methanesulfonic acid (1.1 equiv; 1 M in IPA) made the solution clear (except for traces deposited on the bottom). After a few minutes at about 60 ° C it was cooled to room temperature. A large amount of white material precipitated out. Stir overnight at room temperature. The next day, filtered and dried to give the title compound (3.5 mg). Melting point (tested by DSC) was 331 ° C.

31i) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide hydrobromide

40 μl of acetone was added to N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] Was added to -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide (9.8 mg) and dissolved almost. Hydrobromic acid (1.1 equiv; 1 M in water) was added. After about 2.5 weeks, a small amount of crystals was observed. The stopper was loosened and evaporated overnight. This produced more crystals the next day. Again 50 μl of acetone was added, filtered and dried to afford the title compound.

31j) N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide sulfate

400 μl of acetone was added to N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] To -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide (9.1 mg) was added and almost dissolved. Sulfuric acid (1.1 equiv; 1 M in water) was added. After about 2.5 weeks, large amounts of crystals were observed which were filtered and dried to afford the title compound.

Example 32

N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -3-thiophenecarboxamide

The title compound is obtained from the N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid. Midin-4-yl] -4-methylphenyl} -3-thiophenecarboxamide and 4-piperidinamine were prepared following the general procedure for sulfoxide / sulfone substitution described above. The concentrated reaction mixture was purified via reverse phase HPLC to give the desired compound (0.041 g, 32%) as a light tan powder. The purity of the material indicated by HPLC was greater than 95%. Mp 183.8-187.9 ° C., LC-MS mlz 573 (M + H) ⁺ , 1.79 min (ret. Time).

Example 33

3- [2-[(2-aminoethyl) (methyl) amino] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in THF (5 mL) To a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (50 mg, 0.09 mmol) was added N-methyl-1,2-ethanediamine (0.044 mL, 0.5 mmol). Added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. Flash chromatography (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) then gave the title compound (8.0 mg, 16%).

Example 34

3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-propanamine for the amide formation reaction from the mono] -4-methylbenzoic acid and N, N, N'-trimethyl-1,3-propanediamine for the substitution reaction ( 88%).

Example 35

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-thiophenecarboxamide

4-chloro-2- (2-hydroxy-1-hydroxymethyl-ethylamino) -8- (2,4-difluoro-phenyl) in dioxane / H ₂ O (3: 1, 4.8 mL) N- [4-methyl-3- (4,4,5,5-tetramethyl-1) in a solution of -8H-pyrido [2,3-d] pyrimidin-7-one (40.0 mg, 0.105 mmol) , 3,2-dioxaborolan-2-yl) phenyl] -3-thiophenecarboxamide (53.9 mg, 0.157 mmol) and K ₂ CO ₃ (58.0 mg, 0.420 mmol) were added. The resulting mixture was bubbled with argon for 5 minutes before Pd (PPh ₃ ) ₄ (2.4 mg, 0.0021 mmol) was added. The reaction tube was sealed and heated at "Smith Creator" (Microwave, 150 ° C) for about 15 minutes. The mixture was concentrated in vacuo. Flash chromatography (EtOAc / hexanes, 3: 1) then gave the title compound (50.0 mg, 85%).

Example 36

N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide

The title compound was purified by 4-chloro-8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrid. 3-N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxabo from midin-7 (8H) -one to Suzuki cross-coupling reaction Prepared according to the procedure of Example 35 using rolan-2-yl) benzamide (29.6 mg, 55%).

Example 37

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-isoquinolinecarboxamide trifluoroacetate

37a) 4- (5-amino-2-methyl-phenyl) -8- (2,6-difluoro-phenyl) -2- (2-hydroxy-1-hydroxymethyl-ethylamino) -8H- Pyrido [2,3-d] pyrimidin-7-one

The title compound was prepared according to the procedure of Example 18e from 4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline.

37b) N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-isoquinolinecarboxamide trifluoroacetate

To isoquinoline-3-carboxylic acid (11.5 mg, 0.066 mmol, 1 equiv) was added HATU (38.02 mg, 0.1 mmol, 1.5 equiv) in DMF (250 μl). Then DIPEA (34.84 μl, 0.2 mmol, 3 equiv) was added. The resulting mixture is then left for about 5 minutes before 4- (5-amino-2-methyl-phenyl) -8- (2,6-difluoro-phenyl) -2- (2-hydroxy-1 -Hydroxymethyl-ethylamino) -8H-pyrido [2,3-d] pyrimidin-7-one (30.23 mg, 0.066 mmol, 1 equiv) was added. The resulting mixture was shaken to allow sufficient mixing of the reagents and then left overnight. The solvent was then removed in vacuo. The residue was dissolved in methanol and then placed in aminopropyl SPE and the column was flushed with methanol. The eluate from SPE was then treated with NaOH (2M, 200 μl) and the mixture was left for about 1 hour. It was treated with HCl (2M, 200 μl) and then the solvent was removed under vacuum. The residue was purified by MDAP. LC-MS mlz 609 (M + H) ⁺ , 3.31 min (ret. Time).

Example 38

6-chloro-N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-pyridinecarboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 6-chloro-3-pyridinecarboxylic acid. LC-MS mlz 593 (M + H) ⁺ , 2.99 min (ret. Time).

Example 39

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-hydroxy-1-naphthalenecarboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 2-hydroxy-1-naphthalenecarboxylic acid. LC-MS mlz 624 (M + H) ⁺ , 3.37 min (ret. Time).

Example 40

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -4-fluoro-1-naphthalenecarboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 4-fluoro-1-naphthalenecarboxylic acid. LC-MS mlz 626 (M + H) ⁺ , 3.32 min (ret. Time).

Example 41

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -5-methyl-2-pyrazinecarboxamide trifluoroacetate

The title compound was prepared following the procedure of Example 37b from 5-methyl-2-pyrazinecarboxylic acid. LC-MS mlz 574 (M + H) ⁺ , 2.86 min (ret. Time).

Example 42

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-indole-5-carboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 1H-indole-5-carboxylic acid. LC-MS mlz 597 (M + H) ⁺ , 3.06 min (ret. Time).

Example 43

3-amino-N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] benzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 3-aminobenzoic acid. LC-MS mlz 573 (M + H) ⁺ , 2.77 min (ret. Time).

Example 44

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-indole-7-carboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 1H-indole-7-carboxylic acid. LC-MS mlz 597 (M + H) ⁺ , 3.27 min (ret. Time).

Example 45

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2- (3-methylphenyl) acetamide trifluoroacetate

The title compound was prepared following the procedure of Example 37b from (3-methylphenyl) acetic acid. LC-MS mlz 586 (M + H) ⁺ , 3.15 min (ret. Time).

Example 46

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl] -3.4-dimethylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 3,4-dimethylbenzoic acid. LC-MS mlz 586 (M + H) ⁺ , 3.25 min (ret. Time).

Example 47

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydrate Roxypyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl] -3-fluoro-4-methylbenzamide trifluoroacetate

The title compound was prepared following the procedure of Example 37b from 3-fluoro-4-methylbenzoic acid. LC-MS mlz 590 (M + H) ⁺ , 3.23 min (ret. Time).

Example 48

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3,5-dihydroxy-4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 3,5-dihydroxy-4-methylbenzoic acid. LC-MS mlz 604 (M + H) ⁺ , 2.88 min (ret. Time).

Example 49

2- (2,3-difluorophenyl) -N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] Amino} -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] acetamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from (2,3-difluorophenyl) acetic acid. LC-MS mlz 608 (M + H) ⁺ , 3.12 min (ret. Time).

Example 50

2- (3,5-difluorophenyl) -N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] Amino} -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] acetamide trifluoroacetate

The title compound was prepared following the procedure of Example 37b from (3,5-difluorophenyl) acetic acid. LC-MS mlz 608 (M + H) ⁺ , 3.17 min (ret. Time).

Example 51

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1-methyl-1H-imidazole-4-carboxamide trifluoroacetate

The title compound was prepared from the 1-methyl-1H-imidazole-4-carboxylic acid following the procedure of Example 37b. LC-MS mlz 562 (M + H) ⁺ , 2.65 min (ret. Time).

Example 52

4-[(3-{[3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] amino} -3-oxopropyl) amino] -4-oxobutanoic acid trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 3- (2,5-dioxo-1-pyrrolidinyl) -propanoic acid. LC-MS mlz 607 (M + H) ⁺ , 2.56 min (ret. Time).

Example 53

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-pyrazole-3-carboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 1H-pyrazole-3-carboxylic acid. LC-MS mlz 548 (M + H) ⁺ , 2.74 min (ret. Time).

Example 54

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-thiophenecarboxamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from 2-thiophencarboxylic acid. LC-MS mlz 564 (M + H) ⁺ , 3.03 min (ret. Time).

Example 55

N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-[(2,2,2-trifluoroethyl) oxy] acetamide trifluoroacetate

The title compound was prepared according to the procedure of Example 37b from [(2,2,2-trifluoroethyl) oxy] acetic acid. LC-MS mlz 594 (M + H) ⁺ , 2.96 min (ret. Time).

Example 56

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-propylbenzamide

56a) 4-Methyl-N-propyl-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -benzamide

DMF (5 mL) in 4-methyl-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -benzoic acid (524 mg, 2 mmol, 1 equiv) ) Was added (642 mg, 2 mmol, 1 equiv). DIPEA (700 μl, 4 mmol, 2 equiv) was then added in 100 μl portions. After 10 minutes, propylamine (328 μl, 4 mmol, 2 equiv) was then added and the mixture was stirred at rt overnight. The solvent was then removed in vacuo. The residue was then dissolved in chloroform and purified by aminopropyl SPE. LC-MS mlz 304 (M + H) ⁺ , 3.37 min (ret. Time).

56b) 3- [8- (2,6-difluoro-phenyl) -2-methylsulfanyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -4-methyl-N-propyl-benzamide

4-Chloro-8- (2,6-difluoro-phenyl) -2-methylsulfanyl-8H-pyrido [2,3-d] pyrimidin-7-one (200 mg) in isopropanol (6 mL) , 0.589 mmol, 1 equiv) and 4-methyl-N-propyl-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -benzamide (268 To mg, 0.883 mmol, 1.5 equiv) was added sodium bicarbonate (148 mg, 1.76 mmol, 3 equiv) in water (1.5 mL). The reaction mixture was then purged with nitrogen and then tetrakis (triphenylphosphine) palladium (0) (34 mg, 0.029 mmol, 5 mol%) was added. The mixture was then heated to about 80 ° C overnight. The solvent was then removed in vacuo after the mixture was cooled to room temperature. The residue was then purified on Flashmaster 2 (tradename). LC-MS mlz 481 (M + H) ⁺ , 3.34 min (ret. Time).

56c) 3- [8- (2,6-difluoro-phenyl) -2-methanesulfonyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -4-methyl-N-propyl-benzamide

3- [8- (2,6-difluoro-phenyl) -2-methylsulfanyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- 4-Methyl-N-propyl-benzamide (204 mg, 0.426 mmol, 1 equiv) was suspended in acetonitrile (6 mL). The suspension was added to a stirred suspension of Oxone® (786 mg, 1.28 mmol, 3 equiv) in water (3 mL). The resulting mixture was stirred overnight at about 40 ° C. The reaction mixture was then partitioned between dichloromethane and sodium metabisulfite (10% aqueous solution). After separation of the layers the organics were dried over magnesium sulfate, filtered and evaporated to afford the title compound. LC-MS mlz 513 (M + H) ⁺ , 2.9 min (ret. Time).

56d) 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl) -4-methyl-N-propylbenzamide

The title compound was prepared according to the procedure of Example 31e from the compound from Example 56c and (2-aminoethyl) methylamine. LC-MS mlz 507 (M + H) ⁺ , 2.31 min (ret. Time).

Example 57

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (1-methylethyl) benzamide

The title compound was prepared following the procedure of Example 56 using 2-propanamine for the amide formation reaction and (2-aminoethyl) methylamine for the substitution reaction. LC-MS mlz 507 (M + H) ⁺ , 2.3 min (ret. Time).

Example 58

N-cyclopentyl-3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl) -4-methylbenzamide

The title compound was prepared according to the procedure of Example 56 using cyclopentylamine for the amide formation reaction and (2-aminoethyl) methylamine for the substitution reaction. LC-MS mlz 533 (M + H) ⁺ , 2.43 min (ret. Time).

Example 59

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (phenylmethyl) benzamide

The title compound was prepared according to the procedure of Example 56 using benzylamine for the amide formation reaction and (2-aminoethyl) methylamine for the substitution reaction. LC-MS mlz 555 (M + H) ⁺ , 2.48 min (ret. Time).

Example 60

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was prepared following the procedure of Example 56 using 4-fluoroaniline for the amide formation reaction and (2-aminoethyl) methylamine for the substitution reaction. LC-MS mlz 559 (M + H) ⁺ , 2.55 min (ret. Time).

Example 61

3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared according to the procedure of Example 56 using 1,3-thiazol-2-amine in the amide formation reaction and (2-aminoethyl) methylamine in the substitution reaction. LC-MS mlz 548 (M + H) ⁺ , 2.41 min (ret. Time).

Example 62

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

The title compound was prepared following the procedure of Example 56 using 2-propanamine for the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidinamine in the substitution reaction. LC-MS mlz 589 (M + H) ⁺ , 2.46 min (ret. Time).

Example 63

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-propylbenzamide

The title compound was prepared following the procedure of Example 56 using propanamine for the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidineamine in the substitution reaction. LC-MS mlz 589 (M + H) ⁺ , 2.47 min (ret. Time).

Example 64

N-cyclopentyl-3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6.6-tetramethyl-4-piperidinyl) amino] -7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

The title compound was prepared according to the procedure of Example 56 using cyclopentylamine for the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidinamine for the substitution reaction. LC-MS mlz 615 (M + H) ⁺ , 2.58 min (ret. Time).

Example 65

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide

The title compound was prepared following the procedure of Example 56 using benzylamine for the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidineamine for the substitution reaction. LC-MS mlz 637 (M + H) ⁺ , 2.63 min (ret. Time).

Example 66

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was prepared following the procedure of Example 56 using 4-fluoroaniline for the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidinamine in the substitution reaction. LC-MS mlz 641 (M + H) ⁺ , 2.71 min (ret. Time).

Example 67

3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was subjected to the procedure of Example 56 using 1,3-thiazol-2-amine in the amide formation reaction and 2,2,6,6-tetramethyl-4-piperidinamine in the substitution reaction. Prepared. LC-MS mlz 630 (M + H) ⁺ , 2.57 min (ret. Time).

Example 68

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N- (1-methylethyl) benzamide

The title compound was prepared according to the procedure of Example 56 using 2-propanamine for the amide formation reaction and 4-piperidineamine for the substitution reaction. LC-MS mlz 533 (M + H) ⁺ , 2.42 min (ret. Time).

Example 69

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N-propylbenzamide

The title compound was prepared following the procedure of Example 56 using propanamine for the amide formation reaction and 4-piperidineamine for the substitution reaction. LC-MS mlz 533 (M + H) ⁺ , 2.43 min (ret. Time).

Example 70

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N-cyclopentyl-4-methylbenzamide

The title compound was prepared according to the procedure of Example 56 using cyclopentylamine for the amide formation reaction and 4-piperidineamine for the substitution reaction. LC-MS mlz 559 (M + H) ⁺ , 2.53 min (ret. Time).

Example 71

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N- (phenylmethyl) benzamide

The title compound was prepared according to the procedure of Example 56 using benzylamine for the amide formation reaction and 4-piperidineamine for the substitution reaction. LC-MS mlz 581 (M + H) ⁺ , 2.59 min (ret. Time).

Example 72

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was prepared following the procedure of Example 56 using 4-fluoroaniline for the amide formation reaction and 4-piperidinamine for the substitution reaction. LC-MS mlz 585 (M + H) ⁺ , 2.67 min (ret. Time).

Example 73

3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared according to the procedure of Example 56 using 1,3-thiazol-2-amine in the amide formation reaction and 4-piperidineamine in the substitution reaction. LC-MS mlz 51 (M + H) ⁺ , 2.53 min (ret. Time).

Example 74

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

The title compound was prepared following the procedure of Example 56 using 2-propanamine in the amide formation reaction and (1H-imidazol-2-ylmethyl) amine hydrochloride in the substitution reaction. LC-MS mlz 530 (M + H) ⁺ , 2.25 min (ret. Time).

Example 75

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-propylbenzamide

The title compound was prepared following the procedure of Example 56 using propanamine in the amide formation reaction and (1H-imidazol-2-ylmethyl) amine hydrochloride in the substitution reaction. LC-MS mlz 530 (M + H) ⁺ , 2.26 min (ret. Time).

Example 76

N-cyclopentyl-3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide

The title compound was prepared according to the procedure of Example 56 using cyclopentylamine in the amide formation reaction and (1H-imidazol-2-ylmethyl) amine hydrochloride in the substitution reaction. LC-MS mlz 556 (M + H) ⁺ , 2.38 min (ret. Time).

Example 77

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide

The title compound was prepared following the procedure of Example 56 using benzylamine for the amide formation reaction and (1H-imidazol-2-ylmethyl) amine hydrochloride for the substitution reaction. LC-MS mlz 578 (M + H) ⁺ , 2.44 min (ret. Time).

Example 78

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

The title compound was prepared following the procedure of Example 56 using 4-fluoroaniline for the amide formation reaction and (1H-imidazol-2-ylmethyl) amine hydrochloride for the substitution reaction. LC-MS mlz 582 (M + H) ⁺ , 2.52 min (ret. Time).

Example 79

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide

79a) 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -4-methyl-N-1,3-thiazol-2-ylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine in DMF (15 mL) A solution of -4-yl] -4-methylbenzoic acid (440 mg, 1.00 mmol) was added to DIEA (0.697 mL, 4.0 mmol), HATU (418 mg, 1.1 mmol) and 2-aminothiazole (150 mg, 1.5 mmol). Mixed with. The reaction mixture was stirred overnight, diluted with H ₂ O (0.5 mL) and concentrated in vacuo to remove DMF. Flash chromatography (load column using DCM, mobile phase EtOAc / hexanes) then gave 425 mg (81%) of the title compound as a white solid.

79b) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine in DCM (53 mL) A solution of -4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide (1.65 g, 3.16 mmol) was mixed with mCPBA (0.736 g, 4.75 mmol). The mixture was stirred at room temperature for about 10 minutes and then loaded directly onto the column. Flash chromatography (mobile phase EtOAc / hexanes) then gave 1.38 g (81%) of the title compound as a white solid.

79c) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (127 mL) To a solution of midin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide (1.37 g, 2.54 mmol), Et ₃ N (1.78 mL, 12.7 mmol) and (1H-im already Dazol-2-yl) -methylamine dihydrochloride (0.625 g, 3.81 mmol) was added. The mixture was stirred at rt overnight and concentrated in vacuo. Flash chromatography [mobile phase DCM / DCM (90) + MeOH (7) + NH ₄ OH (3)]] gave 1.23 g (85%) of the title compound as a white solid.

79d) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide methanesulfonate

Using the material prepared in Example 79c above, the reaction vessel was replaced with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7- Amorphous free-base form of oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide ( 11.0 mg) and acetonitrile (250 μL) were charged at room temperature (RT). The mixture was warmed to about 50 ° C. To the warmed mixture is added 1 equivalent of methanesulfonic acid solution (1N in water). The temperature was kept for a few minutes until the solution became clear. The heating was stopped and the mixture cooled to room temperature with shaking. Shaking was continued overnight at room temperature. The product was filtered off and washed with THF. The cake was placed in a crystallization dish and dried under vacuum (house vacuum, 50 ° C., N ₂ release) for several hours. 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide methanesulfonate salt (70.8%, 9.1 mg) was obtained (melt onset temperature determined by DSC) 320 ° C.).

Alternatively, using the material prepared in Example 79c above, the reaction vessel was prepared with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] Free-base of -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide Filled in form (10.05 g) and acetone (201 mL) at room temperature (RT). The mixture was warmed to about 50 ° C and the temperature was maintained for about 15 minutes. To the warmed mixture is added 1 equivalent of methanesulfonic acid solution (1N in water). The temperature was maintained for about 5 minutes until the solution became clear. A small amount of seed material was added to the warmed mixture and the temperature was held at about 50 ° C. for another 30 minutes. The heating was stopped and the mixture was cooled to room temperature with stirring. Stirring was continued for at least 2 hours at room temperature.

Filtration was carried out using a Buechner funnel and the solids were collected on Whatman First filter. The cake was washed with 3x1 volume of acetone and suction dried. The cake was placed in a crystallization dish and dried under vacuum (house vacuum, 50 ° C., N ₂ release) for at least 8 hours to give the title compound (11.14 g, 94.9%).

In the following examples, salts of the title compounds of alternative embodiments were prepared: hydrochloric acid, hydrobromic acid, sulfuric acid (sulfonate), benzoic acid, p-toluenesulfonic acid (methylbenzenesulfonate), citrate, ethane sulfonic acid (ethanesulfo ), Benzenesulfonic acid (benzenesulfonate), fumaric acid (fumarate). Additional salts include camphor sulfonic acid, 1,2-dichlorobenzenesulfonic acid and 1,2-naphthalenesulfonic acid. A single equivalent of acid was introduced to protonate most of the basic nitrogen and reduce the possibility of protonation of other, less basic nitrogens.

79e) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide 4-methylbenzenesulfonate

THF (17.5 mL) was added 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7, from Example 79c. Room temperature in the free-base form (762.2 mg) of 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide Was added to give a clear solution. P-toluenesulfonic acid (0.4 equiv; 1 N in water) was added and the mixture was stirred for several hours. The product was filtered, washed with THF and dried overnight by slowly releasing nitrogen in a 50 ° C. vacuum oven. The yield of the title compound was 32.9% (327.0 mg) (melt onset temperature 259 ° C. as determined by DSC).

79f) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide hydrochloride

Acetone (250 μl) was added with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7, from Example 79c. In amorphous free-base form (12.3 mg) of 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide Was added and the resulting mixture was heated to about 50 ° C. Hydrochloric acid (1.0 equiv; 1 N in 1,4-dioxane) was added. The mixture was cooled to room temperature and shaken for several hours. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. for several hours. The yield of the title compound was 58.1% (7.6 mg) (melt onset temperature less than 50 ° C. as determined by DSC).

Alternatively, acetone (535 μl) was added 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo from Example 79c. Amorphous free-base form of -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (26.6 mg) and the resulting mixture was heated to about 50 ° C. Hydrochloric acid (1.0 equiv; 1 N in water) was added to give a clear solution. Seed crystals were added and the mixture was cooled to room temperature and stirred for several hours. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. overnight. Yield 73.2% (20.7 mg).

79g) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide sulfate

Acetonitrile (250 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7 from Example 79c. Amorphous free-base form of 1,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (11.2 mg) And the resulting mixture was heated to about 50 ° C. Sulfuric acid (1.0 equiv; 1 N in water) was added. The mixture was cooled to room temperature and shaken for several hours. The product was filtered off, washed with acetonitrile and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. for several hours. The yield of the title compound was 72.5% (9.5 mg) (melt onset temperature about 50 ° C. as determined by DSC).

Alternatively, THF (550 μl) was added 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo from Example 79c. Amorphous free-base form of -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (27.4 mg) was added at room temperature to give a clear solution. Sulfuric acid (1.0 equiv; 1 N in water) was added. Seed crystals were added and the mixture was stirred for several hours. The product was filtered off, washed with THF and dried overnight by slowly releasing nitrogen in a 50 ° C. vacuum oven. Yield 88.9% (28.5 mg).

79h) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide hydrobromide

Acetonitrile (300 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7 from Example 79c. Amorphous free-base form of 1,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (16.0 mg) Was added at room temperature to give a mixture. Hydrobromic acid (1.0 equiv; 1 N in water) was added to give a clear solution. The next day a white precipitate was observed. The product was filtered off, washed with acetonitrile and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. overnight. The yield of the title compound was 52.0% (9.5 mg) (melt onset temperature less than 50 ° C. as determined by DSC).

79i) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide citrate

Isopropanol (200 μl) was added with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7, from Example 79c. Addition to the free-base form (10.6 mg) of 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide The resulting mixture was heated to about 50 ° C. Citric acid (1.0 equiv; 1 N in THF) was added. The mixture was cooled to room temperature and shaken for several hours. The product was filtered off, washed with isopropanol and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. for several hours. The yield of the title compound was 61.4% (8.7 mg) (melt onset temperature 179 ° C. as determined by DSC).

Alternatively, isopropanol (502 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo from Example 79c. Free-base form of -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (25.1 mg ) And the resulting mixture was heated to about 50 ° C. The addition of citric acid (1.0 equiv; 1 N in THF) immediately produced a precipitate. Seed crystals were added and the mixture was stirred for several hours. The product was filtered off, washed with isopropanol, and dried overnight by slowly releasing nitrogen in a 50 ° C. vacuum oven. Yield 71.4% (24.0 mg).

79j) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide ethanesulfonate

Acetone (200 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyri To the free-base form (25.1 mg) of Fig. [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide, resulting mixture Was heated to about 50 ° C. Ethanesulfonic acid (1.0 equiv; 1 N in THF) was added and the mixture was stirred for several days. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. overnight. The yield of the title compound was 70.6% (9.1 mg) (melt onset temperature 296 ° C. as determined by DSC).

Alternatively, acetone (501 μl) was added with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8- Add to the free-base form (25.1 mg) of dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide, The resulting mixture was heated to about 50 ° C. Ethanesulfonic acid (1.0 equiv; 1 N in THF) was added. Seed crystals were added and the mixture was stirred for several days. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. overnight. Yield was 78.1% (23.3 mg).

79k) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide benzenesulfonate

Acetone (200 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyri To the free-base form (10.4 mg) of Fig. [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide, resulting mixture Was heated to about 50 ° C. Benzenesulfonic acid (1.0 equiv; 1 N in water) was added to give a clear solution. The mixture was cooled to rt and shaken overnight. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. for several hours. The yield of the title compound was 83.2% (5.8 mg) (melt onset temperature 317 ° C. as determined by DSC).

Alternatively, acetone (494 μl) was added to 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo from Example 79c. Free-base form of -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (24.7 mg ) At room temperature to give a mixture. Benzenesulfonic acid (1.0 equiv; 1 N in water) was added to give a clear solution. Seed crystals were added and the mixture was stirred for several hours. The product was filtered off, washed with acetone and dried by slowly releasing nitrogen in a vacuum oven at 50 ° C. overnight. Yield 83.2% (26.3 mg).

79l) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -methyl-N-1,3-thiazol-2-ylbenzamide fumarate

Isopropanol (200 μl) was added with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7, from Example 79c. Addition to the free-base form (10.5 mg) of 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide The resulting mixture was heated to 50 ° C. Fumaric acid (1.0 equiv; 0.2 N in ethanol) was added. The mixture was cooled to room temperature and shaken for several days. The product was filtered off, washed with isopropanol, and dried overnight by slowly releasing nitrogen in a 50 ° C. vacuum oven. The yield of the title compound was 61.4% (6.0 mg) (melt onset temperature 251 ° C. as determined by DSC).

Alternatively, isopropanol (488 μl) was added with 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo from Example 79c. Free-base form of -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide (24.4 mg ) And the resulting mixture was heated to 50 ° C. The addition of fumaric acid (1.0 equiv; 0.2 N in ethanol) immediately produced a precipitate. Seed crystals were added and the mixture was stirred for several hours. The product was filtered off, washed with isopropanol, and dried overnight by slowly releasing nitrogen in a 50 ° C. vacuum oven. The yield was 63.0% (18.5 mg).

Example 80

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N-propylbenzamide trifluoroacetate

80a) 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -7-oxo-7,8-dihydropyri [2,3-d] pyrimidin-4-yl) -4-methylbenzoic acid

The title compound was purified by 4-chloro-8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [in Suzuki cross-coupling reaction. Prepared according to the procedure of Example 1b using 2,3-d] pyrimidin-7 (8H) -one.

80b) 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyri [2,3-d] pyrimidin-4-yl) -4-methyl-N-propylbenzamide trifluoroacetate

To the acid from Example 80a (32.3 mg, 0.066 mmol, 1 equiv) was added HATU (28.5 mg, 0.075 mmol) in DMF (500 μl). Then DIPEA (34 μL, 0.2 mmol, 3 equiv) was added. The resulting mixture was then left to stand for about 5 minutes before being added to propylamine (6 mg, 0.1 mmol) in DMF (250 μl). The resulting mixture was shaken to allow sufficient mixing of the reagents and then left overnight. The solvent was then removed in vacuo. The residue was dissolved in methanol and then placed in aminopropyl SPE and the column was flushed with methanol. The residue was purified by MDAP to give the above named compound (7.4 mg). LC-MS mlz 524 (M + H) ⁺ , 2.63 min (ret. Time).

Example 81

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (1-methylethyl) benzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using 1-methylethylamine. LC-MS mlz 524 (M + H) ⁺ , 2.62 min (ret. Time).

Example 82

N-cyclobutyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using cyclobutanamine. LC-MS mlz 536 (M + H) ⁺ , 2.7 min (ret. Time).

Example 83

N-cyclopentyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using cyclopentylamine. LC-MS mlz 550 (M + H) ⁺ , 2.78 min (ret. Time).

Example 84

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide trifluoroacetate

The title compound was prepared following the procedure of Example 80b, except using 4-fluoroaniline. LC-MS mlz 576 (M + H) ⁺ , 2.95 min (ret. Time).

Example 85

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide trifluoroacetate

The title compound was prepared following the procedure of Example 80b, except using 1,3-thiazol-2-amine. LC-MS mlz 565 (M + H) ⁺ , 2.75 min (ret. Time).

Example 86

N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using cyclopropylamine. LC-MS mlz 522 (M + H) ⁺ , 2.55 min (ret. Time).

Example 87

N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using cyclopropylmethylamine. LC-MS mlz 536 (M + H) ⁺ , 2.67 min (ret. Time).

Example 88

8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -4- [2-methyl-5- (4-morpholinylcar Carbonyl) phenyl] pyrido [2,3-d] pyrimidin-7 (8H) -one trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using morpholine. LC-MS mlz 552 (M + H) ⁺ , 2.44 min (ret. Time).

Example 89

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N-heptyl-4-methylbenzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using heptylamine. LC-MS mlz 580 (M + H) ⁺ , 3.16 min (ret. Time).

Example 90

N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -4-methylbenzamide (13.5 mg, 0.027 mmol) was dissolved in anhydrous methanol (2 mL) and added to a tube containing nickel chloride hexahydrate (2 mg). The tube was placed under nitrogen atmosphere and cooled to about −15 ° C. using anhydrous ice / acetone bath. Sodium borohydride (2 mg) was then added (substituted after removing nitrogen during this addition) and the solution turned black. The solution was stirred for 1.5 h in anhydrous ice / acetone bath. 1N HCl (4 mL) was added and the solution warmed to room temperature and stirred for about 2 hours under an air atmosphere. Dichloromethane (2 mL) was added to the solution, which was vigorously stirred for 10 minutes, the solution was filtered through a hydrophobic frit packed with celite and washed with additional dichloromethane (2 mL × 2). . The filtrate was concentrated and purified by HPLC to give the title product (1 mg, 8.2%).

Example 91

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (3-pyridinylmethyl) benzamide trifluoroacetate

The title compound was prepared following the procedure of Example 80b, except using (3-pyridinylmethyl) amine. LC-MS mlz 573 (M + H) ⁺ , 2.03 min (ret. Time).

Example 92

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (3-phenylpropyl) benzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using 3-phenyl-1-propanamine. LC-MS mlz 600 (M + H) ⁺ , 2.97 min (ret. Time).

Example 93

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide trifluoroacetate

The title compound was prepared following the procedure of Example 80b, except using (2-phenylethyl) amine. LC-MS mlz 586 (M + H) ⁺ , 2.88 min (ret. Time).

Example 94

3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (phenylmethyl) benzamide trifluoroacetate

The title compound was prepared according to the procedure of Example 80b, except using (phenylmethyl) amine. LC-MS mlz 572 (M + H) ⁺ , 2.83 min (ret. Time).

Example 95

1,1-dimethylethyl (2-{[8- (2,6-difluorophenyl) -4- (5-{[4-fluorophenyl) amino] carbonyl} -2-methylphenyl) -7- Oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} ethyl) methylcarbamate

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) 1,1-dimethylethyl (2-aminoethyl) -methylcarbamate (in a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (50 mg, 0.09 mmol) 0.09 mL, 0.5 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. Flash chromatography (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) then gave the title compound (61 mg, 100%).

Example 96

3- (8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) benzoic acid

96a) 4-chloro-8- (2,4-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one

2,4 in a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (4.2 g, 18.95 mmol) and triethylamine (5.3 ml, 38 mmol) in THF (100 ml) -Difluoroaniline (2.1 ml, 20.58 mmol) was added. The mixture was stirred for 2 hours and methyl {bis [(2,2,2-trifluoroethyl) oxy] phosphoryl} acetate (6.O g, 18.95 mmol) was added. The mixture was stirred for 18 h, diluted with DCM (200 ml) and washed with water (2 × 100 ml). The dried (Na ₂ SO ₄ ) organic phase was filtered and evaporated. Flash chromatography (EtOAc / hexanes, 1: 5) gave the title compound (2.5 g, 40%) as a cream solid. LC-MS mlz 340 (M + H) ⁺ , 3.24 min (ret. Time).

96b) 4-chloro-8- (2,4-difluorophenyl) -2- (methylsulfinyl) pyrido [2,3-d] pyrimidin-7 (8H) -one

4-chloro-8- (2,4-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one (2.5 g) in DCM (100 ml) , 7.6 mmol) was added m-CPBA (2.2 g, 10.2 mmol). The mixture was stirred for 10 minutes and evaporated. Flash chromatography (EtOAc) gave the title compound (2.1 g, 80%) as a yellow solid. LC-MS mlz 356 (M + H) ⁺ , 2.43 min (ret. Time).

96c) 4-chloro-8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrimidine -7 (8H) -on

4-Chloro-8- (2,4-difluorophenyl) -2- (methylsulfinyl) pyrido [2,3-d] pyrimidin-7 (8H) -one (2 in DCM (100 ml) To a solution of .0 g, 5.6 mmol) was added a solution of cerinol (650 mg, 7.1 mmol) in DMF (5 ml). The mixture was stirred for 2 hours, washed with water (2 × 50 ml), dried (Na ₂ SO ₄ ) and evaporated. Flash chromatography (EtOAc / hexanes, 3: 1) gave the title compound (1.1 g, 50%) as a white solid. LC-MS mlz 383 (M + H) ⁺ , 2.45 min (ret. Time).

96d) 3- (8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyri [2,3-d] pyrimidin-4-yl) benzoic acid

4-chloro-8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrimidine-7 (8H) -one (20 mg, 0.047 mmol), 3- (dihydroxyboranyl) benzoic acid (11.8 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.14 mmol), tetrakis (triphenylphosphine A mixture of palladium (2 mg, 0.0017 mmol), dioxane (1.2 ml) and water (0.4 ml) was heated at 150 ° C. for 10 minutes in a closed microwave vessel. The cooled solution was treated with DCM (3 ml) and passed through a silica cartridge (2 g) directly through a hydrophobic frit. The cartridge was eluted with EtOAc and then eluted with EtOAc / MeOH (9: 1) to afford the title compound (20 mg, 80%) as a brown solid. LC-MS mlz 469 (M + H) ⁺ , 2.73 min (ret. Time).

Example 97

3- [2- [2- (aminomethyl) -1H-imidazol-1-yl] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methylbenzoic acid trifluoroacetate

97a) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- General] -4-methylbenzoic acid

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d in CH ₂ Cl ₂ (5.0 ml) To a solution of] pyrimidin-4-yl] -4-methylbenzoic acid (30.0 mg, 0.068 mmol) was added 3-chlorobenzenecarboperoxoic acid (23 mg, 0.103 mmol). The resulting mixture was stirred at rt for 10 min. Flash chromatography (EtOAc / Hex = 1: 1) then gave the title compound (20 mg, 64%). LC-MS (ES) m / z 456 (M + H) ⁺ .

97b) 3- [2- [2- (aminomethyl) -1H-imidazol-1-yl] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid trifluoroacetate

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) To a solution of midin-4-yl] -4-methylbenzoic acid (50 mg, 0.09 mmol) (1H-imidazol-2-ylmethyl) amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL , 1.44 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated and purified by HPLC to give the title product (8 mg, 15%) as an auxiliary component.

Example 98

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methylbenzoic acid trifluoroacetate

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) To a solution of midin-4-yl] -4-methylbenzoic acid (50 mg, 0.09 mmol) (1H-imidazol-2-ylmethyl) amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL , 1.44 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated and purified by HPLC to give the title product (20 mg, 37%) as the main component.

Example 99

3- {8- (2,6-difluorophenyl) -2-[[2- (dimethylamino) ethyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (10 mL) N, N, N'-trimethyl-1,2-ethanediamine (0.057 mL) in a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (50 mg, 0.09 mmol) , 0.44 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. Flash chromatography (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) then gave the title compound (13 mg, 25%).

Example 100

3- {8- (2,6-difluorophenyl) -2-[[2- (dimethylamino) ethyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-propanamine in the amide formation reaction from yl] -4-methylbenzoic acid and N, N, N'-trimethyl-1,2-ethanediamine in the substitution reaction.

Example 101

3- [8- (2,6-difluorophenyl) -2-({3-[(1-methylethyl) amino] propyl} amino) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2--ylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 Prepared from the procedure of Example 79c from -yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide and N- (1-methylethyl) -1,3-propanediamine.

Example 102

3- [8- (2,6-difluorophenyl) -2-({3-[(1,1-dimethylethyl) amino] propyl} amino) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 Prepared from the procedure of Example 79c from -yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide and N- (1,1-dimethylethyl) -1,3-propanediamine. .

Example 103

3- [8- (2,6-difluorophenyl) -2-({2-[(1-methylethyl) amino] ethyl} amino) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 Prepared from the procedure of Example 79c from -yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide and N- (1-methylethyl) -1,2-ethanediamine.

Example 104

3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N-propylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-propylbenzamide (0.04 g, 0.078 mmol), N, N, N'-trimethyl-1,3-propanediamine (0.134 g, 0.115 mmol) and TEA (0.016 g, 0.156 mmol) Combined in CH ₂ Cl ₂ (5 mL) and stirred under argon at room temperature. The solvent was drained under vacuum. In CH ₂ Cl ₂ on silica gel (10 g) to the residue was 6: 1: 0.1 of CH ₂ Cl _2: was performed by flash chromatography, eluting with NH ₄ OH: ethanol. Impurities present in the compound were removed by filtration through a silica gel plug with 3% MeOH / CH ₂ Cl ₂ to afford the title compound as an off-white amorphous solid. Mp 104-109 ° C., LC-MS m / z 549 (M + H) ⁺ , 1.65 min (ret. Time).

Example 105

3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-propylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] 4-Methyl-N-propylbenzamide (0.07 g, 0.13 mmol), N, N-dimethylethylenediamine (0.0173 g, 0.15 mmol) and TEA (0.026 g, 0.26 mmol) were CH ₂ Cl ₂ (5 mL) Combined and stirred at room temperature under argon for 1 h. The solvent was drained under vacuum. 1: 0.1 of CH ₂ Cl _2: ethanol: 6 CH ₂ Cl ₂ on silica gel (10 g) to the residue to perform the flash chromatography, eluting with NH ₄ OH to give the title compound as a white amorphous solid. Mp 139-142 ° C., LC-MS m / z 521 (M + H) ⁺ , 1.61 min (ret. Time).

Example 106

1,1-dimethylethyl {2-[(8- (2,6-difluorophenyl) -4- {2-methyl-5-[(propylamino) carbonyl] phenyl} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-2-yl) amino] ethyl} methylcarbamate

3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] 4-Methyl-N-propylbenzamide (1.59 g, 3.1 mmol) was dissolved in CH ₂ Cl ₂ (140 mL) and stirred under argon at room temperature. 1,1-dimethylethyl (2-aminoethyl) methylcarbamate (0.806 g, 4.65 mmol) and TEA (0.87 mL, 6.2 mmol) were combined in CH ₂ Cl ₂ (10 mL) and added to the sulfone solution. The resulting reaction mixture was stirred overnight under argon. The solvent was drained under vacuum. The residue was subjected to flash chromatography eluting with 0-40% EtOAc / CH ₂ Cl ₂ on silica gel (150 g) to afford the title compound as a white amorphous solid. Melting point 115-118 ° C., LC-MS mlz 607 (M + H) ⁺ , 2.27 min (ret. Time).

Example 107

3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 Prepared from the procedure of Example 79c from -yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide and N, N, N'-trimethyl-1,3-propanediamine.

Example 108

N- [3- (8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) phenyl] acetamide

The title compound was purified by 4-chloro-8- (2,4-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrid. Prepared according to the procedure of Example 96d from midin-7 (8H) -one and [3- (acetylamino) phenyl] boronic acid. LC-MS mlz 482 (M + H) ⁺ , 2.69 min (ret. Time).

Example 109

3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 Prepared from the procedure of Example 79c from -yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide and N, N-dimethyl-1,2-ethanediamine.

Example 110

4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] pyrido [2,3-d] pyrimidin-7 (8H) -one

110a) 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylsulfonyl) pyrido [2,3-d] pyrimidine-7 (8H) -On

4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyridine in CH ₂ Cl ₂ (20.0 mL) To a solution of midin-7 (8H) -one (170.0 mg, 0.41 mmol) was added m-CPBA (224.0 mg, 1.0 mmol). The reaction mixture was stirred at rt for 12 h and concentrated. It was diluted with H ₂ O (5.0 mL) and EtOAc (25.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (hexane: EtOAc = 4: 1) gave the title compound (190.0 mg, 94%). LC-MS mlz 443 (M + H) ⁺ , 2.12 min (ret. Time).

110b) 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] Pyrido [2,3-d] pyrimidin-7 (8H) -one

The title compound was purified by 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylsulfonyl) pyrido [2,3-d] pyrimidine-7 (8H ) -One and from 2,2,6,6-tetramethyl-4-piperidinamine were prepared as described in Example 1d. LC-MS mlz 519 (M + H) ⁺ , 1.8 min (ret. Time).

Example 111

4- (5-amino-methylphenyl) -8- (2,6-difluorophenyl) -2- (4-piperidinylamino) -pyrido [2,3-d] pyrimidine-7 (8H) -On

The title compound was purified by 4- (5-amino-2-methylphenyl) -8- (2,6-difluorophenyl) -2- (methylsulfonyl) pyrido [2,3-d] pyrimidine-7 (8H ) -One and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate prepared as described in Example 2. LC-MS mlz 463 (M + H) ⁺ , 1.73 min (ret. Time).

Example 112

3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) N, N-dimethyl-1,2-ethanediamine (0.009 mL, 0.083 mmol) in a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (15 mg, 0.027 mmol) ) Was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. Flash chromatography (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) then gave the title compound (11 mg, 72%).

Example 113

3- {8- (2,6-difluorophenyl) -2- [4- (methylamino) -1-piperidinyl] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

113a) 1,1-dimethylethyl {1- [8- (2,6-difluorophenyl) -4- (2-methyl-5-{[1-methylethyl) amino] carbonyl} phenyl) -7 -Oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] -4-piperidinyl} methylcarbamate

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-propanamine in the amide formation reaction from the mono] -4-methylbenzoic acid and 1,1-dimethylethyl methyl (4-piperidinyl) carbamate in the substitution reaction It was. LC-MS (ES) m / z 647 (M + H) ⁺ .

113b) 3- {8- (2,6-difluorophenyl) -2- [4- (methylamino) -1-piperidinyl] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide

1,1-dimethylethyl {1- [8- (2,6-difluorophenyl) -4- (2-methyl-5-{[(1-methylethyl) amino] carbonyl in DCM (2 mL) } TFA (0.03 mL) was added to a solution of phenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] -4-piperidinyl} methylcarbamate. Added. The reaction mixture was stirred at rt overnight and quenched with triethylamine (0.5 mL) at -78 ° C. The residue was mixed with H ₂ O (5.0 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) gave the title compound.

Example 114

3- {8- (2,6-difluorophenyl) -2- [4- (methylamino) -1-piperidinyl] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

114a) 1,1-dimethylethyl {1- [8- (2,6-difluorophenyl) -4- (5-{[(4-fluorophenyl) amino] carbonyl} -2-methylphenyl)- 7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] -4-piperidinyl} methylcarbamate

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) 1,1-dimethylethyl methyl (4-piperidinyl) in a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (Example 19b, 10 mg, 0.018 mmol) Carbamate (19 mg, 0.089 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. The title compound was used for next step without purification. LC-MS (ES) m / z 699 (M + H) ⁺ .

114b) 3- {8- (2,6-difluorophenyl) -2- [4- (methylamino) -1-piperidinyl] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

1,1-dimethylethyl {1- [8- (2,6-difluorophenyl) -4- (5-{[(4-fluorophenyl) amino] carbonyl} -2 in DCM (2 mL) TFA (0.03 mL) was added to a solution of -methylphenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] -4-piperidinyl} methylcarbamate. Added. The reaction mixture was stirred at rt overnight and quenched with triethylamine (0.5 mL) at -78 ° C. The residue was mixed with H ₂ O (5.0 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic phases were washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. Then purification via combiflash system (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) gave the title compound (6 mg, 57%, 2 steps).

Example 115

3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in DCM (5 mL) N, N, N'-trimethyl-1,3-propanediamine (0.021 mL) in a solution of midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide (15 mg, 0.027 mmol) , 0.14 mmol) was added. The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo. Flash chromatography (90% CH ₂ Cl ₂ /7% MeOH / 3% NH ₄ OH) gave the title compound (10 mg, 63%).

Example 116

3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide

116a) 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl ] -4-methyl-N- (phenylmethyl) benzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- 4-methylbenzoic acid (0.15 g, 0.342 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and stirred under argon at room temperature. N-benzylamine (0.11 g, 1.03 mmol) was added followed by EDC (0.082 g, 0.41 mmol) and HOBT (0.055 g, 0.41 mmol). The reaction was stirred overnight. The solvent was drained under vacuum and the residue was taken up in EtOAc, washed twice with H ₂ O, once with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was subjected to flash chromatography eluting with 0-1.5% MeOH / CH ₂ Cl ₂ on silica gel (20 g) to afford the title compound. Mp 124-130 ° C., LC-MS m / z 529 (M + H) ⁺ , 2.36 min (ret. Time).

116b) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methyl-N- (phenylmethyl) benzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- 4-methyl-N- (phenylmethyl) benzamide (0.12 g, 0.227 mmol) is dissolved in CH ₂ Cl ₂ (5 mL) and 50-60% of 3-chloroperoxybenzoic acid (0.106 g, 0.34 mmol) Was added and the mixture was stirred for 10 minutes. The solvent was drained off and the residue was taken up in EtOAc, washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The title compound was isolated by flash chromatography eluting with a gradient from hexane to EtOAc on silica gel (20 g) on a crude product containing a small amount of sulfone. Melting point 268 to 27O <0> C, LC-MS m / z 545 (M + H) ⁺ , 1.87 min (ret. Time).

116c) 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] 4-Methyl-N- (phenylmethyl) benzamide (0.084 g, 0.154 mmol) and (1H-imidazol-2-ylmethyl) amine dihydrochloride (0.039 g, 0.23 mmol) were replaced with CH ₂ Cl ₂ (5 mL) and triethylamine (0.7 mL). The resulting mixture was stirred overnight at room temperature under argon. The solvent was drained off in vacuo and the residue was taken up in EtOAc and 1N NaOH. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was subjected to flash chromatography, eluting with CH ₂ Cl ₂ : isopropanol: NH ₄ OH at 6: 1: 0.05 on silica gel (20 g). The isolated material was not pure, on which the chromatography eluting with 0-5% MeOH / CH ₂ Cl ₂ on silica gel (20 g) was again carried out to give the title compound as a white amorphous solid. Melting point 185 to 19O <0> C, LC-MS m / z 578 (M + H) ⁺ , 1.76 min (ret. Time).

Example 117

3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (1-methylethyl) benzamide

The title compound was purified by 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Prepared according to the procedure of Example 19 using 2-propanamine in the amide formation reaction from yl] -4-methylbenzoic acid and N, N-dimethyl-1,2-ethanediamine in the substitution reaction.

Example 118

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (1-methylethyl) benzamide

118a) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylbenzoic acid

Compound 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d in dichloromethane (30 mL) To Pyrimidin-4-yl] -4-methylbenzoic acid (600 mg, 1.32 mmol) was added N, N-diethyl-1,3-propanediamine (0.624 mL, 4.0 mol). The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA gave the title compound (695 mg, 85%). LC-MS mlz 522 (M + H) ⁺ .

118b) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methyl-N- (1-methylethyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in dichloromethane (2 mL) To pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) add HBTU (30 mg, 0.079 mmol) and isopropylamine (0.032 mL, 0.37 mmol) It was. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Chromatography (90% methylene chloride / 7% MeOH / 3% ammonia) gave the title compound (22 mg, 51%). LC-MS mlz 563 (M + H) ⁺ .

Example 119

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-4-dimethylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in dichloromethane (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) in HBTU (30 mg, 0.079 mmol) and methylamine (0.185 mL, 0.37 mmol, 2.0 in THF) M solution) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by chromatography (90% methylene chloride / 7% MeOH / 3% ammonia) gave the title compound (32 mg, 78%). LC-MS mlz 535 (M + H) ⁺ .

Example 120

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N, N, 4-trimethylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in dichloromethane (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) in HBTU (30 mg, 0.079 mmol) and dimethylamine (0.185 mL, 0.37 mmol, 2.0 in THF) M solution) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Chromatography (90% methylene chloride / 7% MeOH / 3% ammonia) gave the title compound (42 mg, 99%). LC-MS mlz 549 (M + H) ⁺ .

Example 121

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in THF (2 mL) To B. [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) was added HBTU (30 mg, 0.079 mmol) and cerinol (35 mg, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (40 mg, 88%). LC-MS mlz 595 (M + H) ⁺ .

Example 122

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-propylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in THF (2 mL) To B. [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) was added HBTU (30 mg, 0.079 mmol) and propylamine (0.031 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (16 mg, 37%). LC-MS mlz 563 (M + H) ⁺ .

Example 123

N-butyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) To pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) was added HBTU (30 mg, 0.079 mmol) and butylamine (0.038 mL, 0.37 mmol). . The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (29 mg, 66%). LC-MS mlz 577 (M + H) ⁺ .

Example 124

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (2-methylpropyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) To pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) add HBTU (30 mg, 0.079 mmol) and isobutylamine (0.038 mL, 0.37 mmol) It was. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (19 mg, 43%). LC-MS mlz 577 (M + H) ⁺ .

Example 125

N-cyclopentyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) was bubbled with nitrogen for 5 minutes before HBTU (30 mg, 0.079 mmol) and cyclopentylamine (0.038 mL, 0.37 mmol) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (21 mg, 47%). LC-MS mlz 589 (M + H) ⁺ .

Example 126

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1,1-dimethylethyl) -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) was charged with HBTU (30 mg, 0.079 mmol) and t-butylamine (0.040 mL, 0.37 mmol). Added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (39 mg, 88%). LC-MS mlz 577 (M + H) ⁺ .

Example 127

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (2,2-dimethylpropyl) -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) HBTU (30 mg, 0.079 mmol) and (2,2-dimethylpropyl) amine (0.045 mL) in pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) , 0.37 mmol) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (39 mg, 86%). LC-MS mlz 591 (M + H) ⁺ .

Example 128

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (2,2,2-trifluoroethyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) in HBTU (30 mg, 0.079 mmol) and (2,2,2-trifluoroethyl) Amine (0.031 mL, 0.37 mmol) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (37 mg, 80%). LC-MS mlz 603 (M + H) ⁺ .

Example 129

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7, 8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-ethyl-4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro in methylene chloride (2 mL) Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (40 mg, 0.074 mmol) in HBTU (30 mg, 0.079 mmol) and ethylamine (0.19 mL, 0.37 mmol, 2.0 in THF) M solution) was added. The mixture was stirred at rt overnight. Solvent was removed by rotary evaporation. Separation by chromatography (90% methylene chloride / 7% MeOH / 3% ammonia) gave the title compound (17 mg, 40%). LC-MS mlz 549 (M + H) ⁺ .

Example 130

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-[(1R) -1,2-dimethylpropyl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and (2R ) -3-methyl-2-butanamine (10.5 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (14 mg, 40%). LC-MS mlz 591 (M + H) ⁺ .

Example 131

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-[(1S) -1,2-dimethylpropyl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and (2S ) -3-methyl-2-butanamine (10.5 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (14 mg, 40%). LC-MS mlz 591 (M + H) ⁺ .

Example 132

N- (cyclopentylmethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 1- Cyclopentylmethanamine (9.9 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (10 mg, 33%). LC-MS mlz 603 (M + H) ⁺ .

Example 133

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (2-fluoroethyl) -4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 2- Fluoroethanamine hydrochloride (10 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (9 mg, 32%). LC-MS mlz 567 (M + H) ⁺ .

Example 134

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- [2- (methyloxy) ethyl] benzamidetrifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 2- (Methyloxy) ethanamine (8.6 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (11 mg, 38%). LC-MS mlz 579 (M + H) ⁺ .

Example 135

N- (cyclohexylmethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and (cyclo Hexylmethyl) amine (13.0 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (10 mg, 32%). LC-MS mlz 617 (M + H) ⁺ .

Example 136

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-[(5-methyl-2-furanyl) methyl] benzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and [( 5-methyl-2-furanyl) methyl] amine (11.2 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (13 mg, 42%). LC-MS mlz 615 (M + H) ⁺ .

Example 137

N-cyclobutyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and cyclobutyl Amine (8.5 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (10 mg, 35%). LC-MS mlz 575 (M + H) ⁺ .

Example 138

N- (cyclopropylmethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and (cyclo Propylmethyl) amine (10.3 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (9 mg, 31%). LC-MS mlz 575 (M + H) ⁺ .

Example 139

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (2-thienylmethyl) benzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and (2 -Thienylmethyl) amine (15.1 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (11 mg, 36%). LC-MS mlz 617 (M + H) ⁺ .

Example 140

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7, 8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N, N-diethyl-4-methylbenzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and diethyl Amine (7.4 μL, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (7 mg, 24%). LC-MS mlz 577 (M + H) ⁺ .

Example 141

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (tetrahydro-2H-pyran-4-ylmethyl) benzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and (tetra Hydro-2H-pyran-4-ylmethyl) amine (15.4 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (8 mg, 26%). LC-MS mlz 617 (M + H) ⁺ .

Example 142

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (tetrahydro-2-furanylmethyl) benzamide trifluoroacetate

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and (tetra Hydro-2-furanylmethyl) amine (10.3 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (9 mg, 30%). LC-MS mlz 605 (M + H) ⁺ .

Example 143

N-cyclohexyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and cyclohexane Amine (11.5 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (9 mg, 30%). LC-MS mlz 603 (M + H) ⁺ .

Example 144

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- [2- (ethylthio) ethyl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and [2 -(Ethylthio) ethyl] amine hydrochloride (14.2 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (7 mg, 23%). LC-MS mlz 607 (M + H) ⁺ .

Example 145

N- (2-cyanoethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 3- Aminopropanenitrile hydrochloride (9.3 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (6 mg, 21%). LC-MS mlz 560 (M + H) ⁺ .

Example 146

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- [2- (1H-imidazol-4-yl) ethyl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and [2 -(1H-imidazol-4-yl) ethyl] amine (22.2 mg, 0.2 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (26 mg, 85%). LC-MS mlz 615 (M + H) ⁺ .

Example 147

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-phenylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and aniline ( 9.1 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. 5 mL dichloromethane and 2 mL water were added to the mixture and stirred for 3 minutes. The organic layer was loaded onto a silica gel column. Chromatography (90% methylene chloride / 7% MeOH / 3% ammonia) gave the title compound (9 mg, 30%). LC-MS mlz 597 (M + H) ⁺ .

Example 148

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-[(1R) -1-phenylethyl] benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and [( 1R) -1-phenylethyl] amine (12.9 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (14 mg, 45%). LC-MS mlz 625 (M + H) ⁺ .

Example 149

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-[(1S) -1-phenylethyl] benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and [( 1S) -1-phenylethyl] amine (12.9 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (14 mg, 45%). LC-MS mlz 625 (M + H) ⁺ .

Example 150

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -2-methyl-N-1,3-thiazol-2-ylbenzamide

150a) 4-chloro-8- (2,6-difluorophenyl) -2- (methylsulfinyl) pyrido [2,3-d] pyrimidin-7 (8H) -one

Compound 4-chloro-8- (2,6-difluorophenyl) -2- (methylthio) pyrido [2,3-d] pyrimidin-7 (8H) -one in dichloromethane (100 mL) ( 1.70 g, 5.0 mmol) was added mCPBA (1.16 g, 7.5 mmol). The mixture was stirred at rt for 10 min. Chromatography using hexanes / ethyl acetate gave the title compound (1.59 g, 89%). LC-MS mlz 356 (M + H) ⁺ .

150b) 4-chloro-2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) pyrido [2,3-d] pyrimidine-7 (8H) -On

Compound 4-Chloro-8- (2,6 ~ difluorophenyl) -2- (methylsulfinyl) -pyrido [2,3-d] pyrimidine-7 (8H)-in dichloromethane (89.4 mL) To warm (1.59 g, 4.47 mmol) was added N, N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine (1.26 μl, 8.94 mmol). The mixture was stirred at rt overnight. Some white precipitate formed during the reaction. After filtration, washing with ethyl acetate / dichloromethane / methanol gave the title compound (1.028 g, 60%). LC-MS mlz 383 (M + H) ⁺ .

150c) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -2-methylbenzoic acid

Compound 4-chloro-2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) pyrido [2 in dioxane (4.5 mL) and water (1.5 mL) , 3-d] pyrimidin-7 (8H) -one (176 mg, 0.418 mmol) in 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) benzoic acid (173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) and tetrakis (triphenylphosphine) palladium (0) (24.2 mg, 0.0259 mmol) were added. The mixture was heated by microwave at 150 ° C. for 15 minutes. The mixture was filtered. Separation by HPLC with TFA gave the title compound (238 mg, 99%). LC-MS mlz 522 (M + H) ⁺ .

150d) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -2-methyl-N-1,3-thiazol-2-ylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 1, 3-thiazol-2-amine (10.0 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (9 mg, 30%). LC-MS mlz 604 (M + H) ⁺ .

Example 151

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -2-methyl-N-phenylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and aniline ( 9.1 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (18 mg, 60%). LC-MS mlz 597 (M + H) ⁺ .

Example 152

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (4-fluorophenyl) -2-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and 4- Fluoroaniline (9.6 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (14 mg, 46%). LC-MS mlz 615 (M + H) ⁺ .

Example 153

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -2-methyl-N-propylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and propylamine (8.2 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (15 mg, 53%). LC-MS mlz 563 (M + H) ⁺ .

Example 154

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -2-methyl-N- (2-methylpropyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and isobutyl Amine (10.0 μL, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (12.6 mg, 44%). LC-MS mlz 577 (M + H) ⁺ .

Example 155

N-cyclopropyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -2-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and cyclopropyl Amine (6.9 μl, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (13.5 mg, 48%). LC-MS mlz 561 (M + H) ⁺ .

Example 156

N- (cyanomethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -2-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -2-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and aminoaceto Nitrile (9.3 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (9.1 mg, 33%). LC-MS mlz 560 (M + H) ⁺ .

Example 157

N- (2-amino-2-oxoethyl) -3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and glycineamide (11.1 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (9 mg, 31%). LC-MS mlz 578 (M + H) ⁺ .

Example 158

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- [2- (methylamino) -2-oxoethyl] benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (26 mg, 0.05 mmol) in HBTU (28 mg, 0.075 mmol), triethylamine (21.1 μl, 0.15 mmol) and N ¹ -Methylglycineamide (12.5 mg, 0.1 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (9 mg, 30%). LC-MS mlz 592 (M + H) ⁺ .

Example 159

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-3-pyridinylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.3 mg, 0.06 mmol) in HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and 3- Aminopyridine (11.3 mg, 0.08 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (3.3 mg, 9%). LC-MS mlz 598 (M + H) ⁺ .

Example 160

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.3 mg, 0.06 mmol) in HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and 4- Fluoroaniline (8.64 μl, 0.08 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (10 mg, 27%). LC-MS mlz 615 (M + H) ⁺ .

Example 161

N-cyclopropyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.3 mg, 0.06 mmol) in HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and cyclopropyl Amine (6.24 μL, 0.08 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (10 mg, 30%). LC-MS mlz 562 (M + H) ⁺ .

Example 162

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (1-methylpropyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.3 mg, 0.06 mmol) in HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and sec- Butylamine (12.12 μl, 0.08 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (3.2 mg, 9%). LC-MS mlz 577 (M + H) ⁺ .

Example 163

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N- (1-methylethyl) benzamide

163a) 4-chloro-8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) pyrido [2,3-d] pyrid Midin-7 (8H) -on

Compound 4-chloro-8- (2,6-difluorophenyl) -2- (methylsulfinyl) pyrido [2,3-d] pyrimidin-7 (8H) -one in dichloromethane (80 mL) To (1.39 g, 3.9 mmol) was added 4-methyl-1,4'-bipiperidine (0.75 g, 5.85 mol) and triethylamine (1.03 mL, 11.7 mmol). The mixture was stirred at -20 ° C overnight. After filtration and concentration, the crude was purified by flash chromatography to give the title compound (0.904 g, 51%). LC-MS mlz 474 (M + H) ⁺ .

163b) 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (GSK1080365A)

Compound 4-chloro-8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidine-1'- in dioxane (3 mL) and water (1 mL) Yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (47.5 mg, 0.1 mmol) in 6-methyl-3- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) benzoic acid (38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (4.6 mL, 0.005 mmol) Added. The mixture was heated by microwave at 150 ° C. for 15 minutes. After concentration of the mixture, DMSO (0.75 mL) and water (0.25 mL) were added. Separation by HPLC gave the title compound (39 mg, 68%). LC-MS mlz 574 (M + H) ⁺ .

163c) 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N- (1-methylethyl) benzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and isopropylamine (7.03 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (16.4 mg, 48.5%). LC-MS mlz 615 (M + H) ⁺ .

Example 164

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N, 4-dimethylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and methylamine (41.3 μl, 0.0825 mmol, 2M solution in THF) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (7.2 mg, 22%). LC-MS mlz 587 (M + H) ⁺ .

Example 165

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N, N, 4-trimethylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and dimethylamine (41.3 μl, 0.0825 mmol, 2M solution in THF) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (11.5 mg, 35%). LC-MS mlz 601 (M + H) ⁺ .

Example 166

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-propylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and propylamine (6.78 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (18.6 mg, 55%). LC-MS mlz 615 (M + H) ⁺ .

Example 167

N-butyl-3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and butylamine (8.19 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (18.7 mg, 55%). LC-MS mlz 629 (M + H) ⁺ .

Example 168

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N- (2-methylpropyl) benzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and isobutylamine (8.28 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (18.4 mg, 53%). LC-MS mlz 629 (M + H) ⁺ .

Example 169

N-cyclopentyl-3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclopentanamine (8.15 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (16.9 mg, 48%). LC-MS mlz 641 (M + H) ⁺ .

Example 170

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N- (1,1-dimethylethyl) -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and t-butylamine (8.71 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (17.6 mg, 51%). LC-MS mlz 629 (M + H) ⁺ .

Example 171

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N- (2,2-dimethylethyl) -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 2,2-dimethyl-1-propanamine (8.65 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (17.8 mg, 50%). LC-MS mlz 643 (M + H) ⁺ .

Example 172

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N- (2,2,2-trifluoroethyl) benzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 2,2,2-trifluoroethanamine (6.56 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (24.6 mg, 68%). LC-MS mlz 655 (M + H) ⁺ .

Example 173

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N-ethyl-4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and ethylamine (41.3 μl, 0.0825 mmol, 2M solution in THF) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (26.2 mg, 78%). LC-MS mlz 601 (M + H) ⁺ .

Example 174

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 4-fluoroaniline (7.92 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (26.4 mg, 72%). LC-MS mlz 667 (M + H) ⁺ .

Example 175

N-cyclobutyl-3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclobutanamine (7.04 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (24.8 mg, 72%). LC-MS mlz 627 (M + H) ⁺ .

Example 176

N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo- 7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 1-cyclopropylmethanamine (7.15 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (6.2 mg, 18%). LC-MS mlz 627 (M + H) ⁺ .

Example 177

3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N- (2-fluoroethyl) -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 2-fluoroethylamine hydrochloride (8.09 mg, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (11.1 mg, 33%). LC-MS mlz 619 (M + H) ⁺ .

Example 178

N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide

Compound 3- [8- (2,6-difluorophenyl) -2- (4-methyl-1,4'-bipiperidin-1'-yl) -7-oxo-7 in DMF (0.5 mL) , 8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzoic acid (31.6 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclopropylamine (5.71 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (13.8 mg, 41%). LC-MS mlz 613 (M + H) ⁺ .

Example 179

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-4-methyl-N- (1-methylethyl) benzamide

179a) 1,1-dimethylethyl 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoate trifluoroacetate

Compound 4-chloro-2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) pyrido [2 in dioxane (15 mL) and water (5 mL) , 3-d] pyrimidin-7 (8H) -one (600 mg, 1.422 mmol) in 1,1-dimethylethyl 3-fluoro-4-methyl-5- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) benzoate (542 mg, 2.132 mol), potassium carbonate (590 mg, 4.26 mmol) and tetrakis (triphenylphosphine) palladium (O) (82 mg, 0.071 mmol) was added. The mixture was heated by microwave at 150 ° C. for 15 minutes. The mixture was filtered. Separation by HPLC with TFA afforded the crude title compound.

179b) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid trifluoroacetate

Crude compound 1,1-dimethylethyl 3- [2-{[3- (diethylamino) -propyl] amino} -8- (2,6-difluorophenyl) in dichloromethane (1.5 mL, 23.3 mmol) TFA (0.703 mL, 9.5 mmol) in -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoate trifluoroacetate ) And triethylsilane (0.281 mL, 1.82 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA gave the title compound (301 mg, 40%, two step yield). LC-MS mlz 540 (M + H) ⁺ .

179c) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -5-fluoro-4-methyl-N- (1-methylethyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid trifluoroacetate (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine ( 15.5 μl, 0.11 mmol) and isopropylamine (7.03 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (19.3 mg, 60%). LC-MS mlz 581 (M + H) ⁺ .

Example 180

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-N, 4-dimethylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and methylamine (41.5 μl, 0.0825 mmol, 2M solution in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (9.6 mg, 31.5%). LC-MS mlz 553 (M + H) ⁺ .

Example 181

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-4-methyl-N-propylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and propylamine (6.78 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (18.7 mg, 58%). LC-MS mlz 581 (M + H) ⁺ .

Example 182

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-N- (4-fluorophenyl) -4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 4-fluoroaniline (7.92 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (20.1 mg, 58%). LC-MS mlz 633 (M + H) ⁺ .

Example 183

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-4-methyl-N-1,3-thiazol-2-ylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 2-aminothioazole (8.26 mg, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (15.6 mg, 46%). LC-MS mlz 622 (M + H) ⁺ .

Example 184

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-4-methyl-N-phenylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and aniline (7.51 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (14.1 mg, 42%). LC-MS mlz 615 (M + H) ⁺ .

Example 185

N-cyclopropyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclopropylamine (5.71 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (20 mg, 60%). LC-MS mlz 579 (M + H) ⁺ .

Example 186

N-cyclopentyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclopentanamine (8.15 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (18.2 mg, 56%). LC-MS mlz 607 (M + H) ⁺ .

Example 187

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1,1-dimethylethyl) -5-fluoro-4-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] -5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and t-butylamine (8.71 μl, 0.0825 mmol) were added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (14.8 mg, 46%). LC-MS mlz 595 (M + H) ⁺ .

Example 188

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-propylbenzamide

188a) 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] benzoic acid

Compound 4-chloro-2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) pyrido [2 in dioxane (12 mL) and water (4 mL) , 3-d] pyrimidin-7 (8H) -one (168.75 mg, 0.40 mmol) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Benzoic acid (148.85 mg, 0.60 mol), potassium carbonate (208 mg, 1.20 mmol) and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) were added. The mixture was heated by microwave at 150 ° C. for 15 minutes. The mixture was concentrated. It was mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC gave the title compound (147 mg, 72%). LC-MS mlz 508 (M + H) ⁺ .

188b) 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -N-propylbenzamide

Compound 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (28 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and propylamine (6.78 μl, 0.0825 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (16.1 mg, 53%). LC-MS mlz 549 (M + H) ⁺ .

Example 189

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1-methylethyl) benzamide

Compound 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (28 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and isopropylamine (7.03 μl , 0.0825 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (16.1 mg, 53%). LC-MS mlz 549 (M + H) ⁺ .

Example 190

N-cyclopropyl-4- (2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] benzamide

Compound 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (28 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and cyclopropylamine (5.71 μl , 0.0825 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (17.8 mg, 59%). LC-MS mlz 547 (M + H) ⁺ .

Example 191

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (4-fluorophenyl) benzamide

Compound 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (28 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 4-fluoroaniline ( 7.92 μl, 0.0825 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (15.8 mg, 48%). LC-MS mlz 601 (M + H) ⁺ .

Example 192

4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-1,3-thiazol-2-ylbenzamide

Compound 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (28 mg, 0.055 mmol) in HBTU (25 mg, 0.066 mmol), triethylamine (15.5 μl, 0.11 mmol) and 2-aminothiazole ( 8.26 mg, 0.0825 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (5.8 mg, 18%). LC-MS mlz 590 (M + H) ⁺ .

Example 193

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-methylbenzamide

193a) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] benzoic acid (GSK1120344A)

Compound 4-chloro-2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) pyrido [2 in dioxane (15 mL) and water (5 mL) , 3-d] pyrimidin-7 (8H) -one (210.5 mg, 0.50 mmol) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Benzoic acid (125 mg, 0.75 mol), potassium carbonate (210 mg, 1.20 mmol) and tetrakis (triphenylphosphine) palladium (0) (29 mg, 0.025 mmol) were added. The mixture was heated by microwave at 150 ° C. for 15 minutes. The mixture was concentrated and then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC gave the title compound (467 mg, 32%). LC-MS mlz 508 (M + H) ⁺ .

193b) 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -N-methylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and methylamine (45 μl, 0.09 mmol, 2M solution in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with a SPE amine cartridge gave the title compound (9.6 mg, 31%). LC-MS mlz 521 (M + H) ⁺ .

Example 194

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-propylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and propylamine (7.40 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (20.8 mg, 63%). LC-MS mlz 549 (M + H) ⁺ .

Example 195

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1-methylethyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) To [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and isopropylamine (7.67 μl , 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge yielded the title compound (20.5 mg, 62%). LC-MS mlz 549 (M + H) ⁺ .

Example 196

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (4-fluorophenyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and 4-fluoroaniline ( 8.64 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (20 mg, 55.5%). LC-MS mlz 601 (M + H) ⁺ .

Example 197

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-1,3-thiazol-2-ylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and 2-aminothiazole ( 9.01 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (20.5 mg, 58%). LC-MS mlz 590 (M + H) ⁺ .

Example 198

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-phenylbenzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and aniline (8.21 μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with an SPE amine cartridge gave the title compound (17.2 mg, 49%). LC-MS mlz 583 (M + H) ⁺ .

Example 199

3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- (1,1-dimethylethyl) benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and t-butylamine (9.54 Μl, 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (17.4 mg, 52%). LC-MS mlz 563 (M + H) ⁺ .

Example 200

N-cyclopentyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and cyclopentanamine (8.91 μl , 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (6.0 mg, 17%). LC-MS mlz 575 (M + H) ⁺ .

Example 201

N-cyclopropyl-3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl] benzamide

Compound 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyri in DMF (0.5 mL) In [2,3-d] pyrimidin-4-yl] benzoic acid (30 mg, 0.06 mmol) in HBTU (27 mg, 0.072 mmol), triethylamine (16.9 μl, 0.12 mmol) and cyclopropylamine (6.24 μl , 0.09 mmol) was added. The mixture was stirred at rt overnight. Separation by HPLC with TFA followed by neutralization with SPE amine cartridge gave the title compound (15 mg, 46.6%). LC-MS mlz 547 (M + H) ⁺ .

Example 202

1,1-dimethylethyl (2-{[8- (2,6-difluorophenyl) -4- (2-methyl-5-{[(2-phenylethyl) amino] carbonyl} phenyl) -7 -Oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} ethyl) methylcarbamate

202a) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methyl-N- (2-phenylethyl) benzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in dichloromethane (5 mL) To a solution of midin-4-yl] -4-methylbenzoic acid (220 mg, 0.50 mmol) (2-phenylethyl) amine (69.1 μl, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (6.8 mg, 0.05 mmol) and Et ₃ N (281 μl, 2.0 mmol) were added. The reaction mixture was stirred at rt for 20 h. It was then quenched with H ₂ O, extracted with DCM, dried over Na ₂ SO ₄ , filtered, concentrated and subjected to flash chromatography to give 202 mg (74%) of the title compound.

202b) 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methyl-N- (2-phenylethyl) benzamide

3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyridine in dichloromethane (7 mL) To a solution of midin-4-yl] -4-methyl-N- (2-phenylethyl) benzamide (200 mg, 0.369 mmol) was added m-CPBA (86.1 mg, 0.553 mmol). The reaction mixture was stirred at rt for 10 min. The reaction mixture was then subjected to flash chromatography to give 157 mg (76%) of the title compound.

202c) 1,1-dimethylethyl (2-{[8- (2,6-difluorophenyl) -4- (2-methyl-5-{[(2-phenylethyl) amino] carbonyl} phenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-2-yl] amino} ethyl) methylcarbamate

3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] in dichloromethane (11 mL) 1,1-dimethylethyl (2-aminoethyl) methylcarbamate (75 in a solution of pyrimidin-4-yl] -4-methyl-N- (2-phenylethyl) benzamide (156 mg, 0.28 mmol) Μl, 0.42 mmol) and triethylamine (78.7 μl, 0.56 mmol) were added. The reaction mixture was stirred at rt for 16 h and then subjected to flash chromatography to yield 147 mg (79%) of the title compound.

How to treat

Compounds of Formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1, or pharmaceutically thereof Acceptable salts, solvates or physiologically functional derivatives are any disease state in humans or other mammals that is exacerbated or caused by excessive or upregulated cytokine production by mammalian cells such as monocytes and / or macrophages and the like. It can be used in the manufacture of a medicament for the prophylactic or curative treatment of.

For the purposes of the present invention, of formulas I and Ia, II and IIa, III and IIIa, IV and IVa, V and Va, VI, VIa to VIi, VIII, VIIIa, IX, IXa, A, A1, B and B1 All compounds will be referred to as compounds of Formula (I) unless otherwise indicated.

Compounds of formula (I) are used for treatment because they can inhibit pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF. IL-1, IL-6, IL-8, and TNF affect a wide variety of cells and tissues, and not only the cytokines but also other leukocyte-derived cytokines are important essential inflammatory mediators of a wide variety of disease states and symptoms. Inhibition of such pro-inflammatory cytokines is beneficial for controlling, reducing and alleviating many of the disease states.

Accordingly, the present invention provides a method of treating cytokine mediated disease comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to inhibit cytokine.

Compounds of formula (I) can inhibit inducible pro-inflammatory proteins such as COX-2 (also referred to by many other names such as prostaglandin endoperoxide synthase-2 (PGHS-2)) for use in therapy do. Pre-inflammatory lipid mediators of this cyclooxygenase (CO) pathway are produced by inducible COX-2 enzymes. Thus, modulating COX-2, which is responsible for products derived from arachidonic acid (eg, prostaglandins), affects a wide variety of cells, and tissue is an important essential inflammatory mediator of a wide variety of disease states and symptoms. Expression of COX-1 is not affected by the compound of formula (I). Such selective inhibition of COX-2 may inhibit prostaglandins, which are essential for the cytoprotective effect, to mitigate or reduce the possibility of ulceration associated with inhibition of COX-1. Thus, inhibition of the pro-inflammatory mediators is beneficial for controlling, reducing or alleviating many of the disease states. In particular, these inflammatory mediators, in particular prostaglandins, are associated with pain, such as sensitization of pain receptors, or edema. Thus, the pain management aspect includes the treatment of neuromuscular pain, headache, cancer pain and arthritis pain. Compounds of formula (I) or pharmaceutically acceptable salts thereof are used for prevention or treatment by inhibiting the synthesis of COX-2 enzymes in humans or other mammals.

Accordingly, the present invention provides a method of inhibiting the synthesis of COX-2, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides methods of prophylactic treatment by inhibiting the synthesis of COX-2 enzymes in humans or other mammals.

In particular, the compounds of formula (I) or pharmaceutically acceptable salts thereof are excessively or upregulated by IL-1, IL- by human or other mammalian cells (eg, mononuclear cells and / or macrophages, etc.). 6, used to prevent or treat any disease state exacerbated or caused by the production of IL-8 or TNF.

Thus, in another aspect, the invention comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said IL-1 in said mammal It relates to a method for suppressing the production of.

There are a number of disease states in which the production of excessive or upregulated IL-1 is associated with exacerbation and / or induction of the disease. Such disease states include rheumatoid arthritis, osteoarthritis, meningitis, ischemic and hemorrhagic stroke, neurotrauma / obstructive head injury, stroke, endotoxemia and / or toxic shock syndrome, other acute or chronic inflammatory disease states such as endotoxins Induced inflammatory response or inflammatory bowel disease, tuberculosis, atherosclerosis, myopathy, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, lighter syndrome, gout, traumatic arthritis, rubella arthritis and acute synoviitis. Recent evidence also relates to IL-1 activity against diabetes, pancreatic β cell disease and Alzheimer's disease.

Uses of CSAID inhibitor compounds in the treatment of CSBP mediated disease conditions may include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease (as mentioned above), Parkinson's disease, multiple sclerosis, and the like. Do not.

In a further aspect, the present invention comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, thereby inhibiting the production of TNF in said mammal. It is about a method.

Excessive or upregulated production of TNF is associated with the mediation or exacerbation of many diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms, sepsis, septic shock, endotoxin shock , Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, chronic lung inflammatory disease and chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, heart, brain and kidney reperfusion injury, graft-versus-host Reaction, allograft rejection, infections such as fever and myalgia due to influenza infection, brain infections including encephalitis (including HIV-induced forms), cerebral malaria, meningitis, ischemic and hemorrhagic stroke, cachexia accompanying infection or malignancy Cachexia accompanying AIDS, AIDS, ARC (AIDS-related complications), keloid formation, Scar tissue formation, inflammatory bowel disease, Crohn's disease, ulcerative colitis and fever.

Compounds of formula (I) are also useful for the treatment of viral infections, which viruses will be sensitive to upregulation by TNF or will induce the in vivo production of TNF. Viruses contemplated for treatment in the present invention are those that are sensitive to producing TNF as a result of infection, or to direct or indirect (eg, by reducing replication) inhibition by TNF inhibition-compound I. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and herpes viruses (eg, herpes zoster and herpes simplex virus, etc.). Do not. Thus, in a further aspect, the present invention comprises treating a mammal infected with human immunodeficiency virus (HIV) with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to inhibit TNF. It is about a method.

In addition, IL-6 and IL-8 are produced during infection with rhinoviruses (HRV) and are known to act as a etiology for exacerbation of asthma associated with common cold and HRV infections (Turner et al. (1998), Clin Infec. Dis., Vol. 26, p 840; Teren et al. (1997), Am. J. Respir. Crit. Care Med., Vol. 155, p 1362; Runberg et al. (1997). ), Am. J. Respir. Crit. Care Med. Vol. 156, p 609 and Zhu et al, J Clin. Invest (1996), 97: 421). It has also been demonstrated that IL-6 and IL-8 are produced when lung epithelial cells are infected with HRV in vitro (Subauste et al., J. Clin. Invest. 1995, 96: 549). Epithelial cells represent the site of primary infection of HRV. Thus, another aspect of the invention is a method of treatment that does not necessarily affect the virus itself, which reduces inflammation associated with rhinovirus infection.

The compounds of formula (I) can also be used in connection with veterinary treatment of non-human mammals in need of inhibition of the production of TNF. TNF mediated diseases for curative or prophylactic treatment in animals include the disease states as mentioned above, in particular viral infections. Examples of such viruses include lentiviral infections, such as equine infectious anemia virus, goat arthritis virus, visna virus or Maedi virus, or retrovirus infections (eg feline immunodeficiency virus (FIV), bovine immunodeficiency virus or canine). Immunodeficiency virus, or other retroviral infections), but is not limited to these.

Compounds of formula (I) also include local disease conditions such as inflammatory joints, eczema, psoriasis and other inflammatory skin symptoms, such as sunburn, mediated or exacerbated by excessive production of cytokines (eg, by IL-1 or TNF, respectively); Inflammatory eye symptoms (including conjunctivitis); It can be used topically for the treatment or prevention of fever, pain and other symptoms associated with inflammation. Periodontal disease is also associated with cytokine production locally and systemically. Thus, the use of the compounds of formula I to control inflammation associated with cytokine production in dental diseases such as gingivitis and periodontitis constitute another aspect of the present invention.

Compounds of formula I have also been found to inhibit the production of IL-8 (interleukin-8, NAP). Thus, in a further aspect, the present invention comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein It relates to a method of suppressing the production of 8.

There are a number of disease states in which excessive or upregulated production of IL-8 is associated with exacerbation and / or induction of disease. Such diseases are characterized by extensive neutrophil infiltration, such as psoriasis, inflammatory bowel disease, asthma, heart, brain and kidney reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with an increase in IL-8 production, which is responsible for the chemotaxis of neutrophils to inflammatory sites. Unlike other inflammatory cytokines (IL-1, TNF and IL-6), IL-8 exhibits a unique activity that promotes neutrophil chemotaxis and activation. Thus, inhibition of IL-8 production will directly reduce neutrophil infiltration.

Compounds of formula (I) reduce the disease state by inhibiting the production of cytokines, particularly IL-1, IL-6, IL-8 or TNF, and downregulating their levels to normal levels, or in some cases below normal levels, or It is administered in an amount sufficient to prevent it. In the present invention, abnormal levels of IL-1, IL-6, IL-8 or TNF are for example, (i) at least 1 pg / ml free (not bound to cells) IL-1, IL-6, The level of IL-8 or TNF; (ii) any cell related IL-1, IL-6, IL-8 or TNF; Or (iii) the presence of IL-1, IL-6, IL-8 or TNF mRNA above the basal level in cells or tissues in which IL-1, IL-6, IL-8 or TNF is produced, respectively.

The discovery that compounds of formula (I) are inhibitors of cytokines, in particular IL-1, IL-6, IL-8 and TNF, has shown in the in vitro assays described herein that compounds of formula (I) are involved in the production of IL-1, IL-8 and TNF. It is based on the effect.

As used herein, the term "inhibition of production of IL-1 (IL-6, IL-8 or TNF)"

a) normal or normal levels by inhibiting the release of cytokines by all cells (including mononuclear cells or macrophages, etc.) by excessively in vivo levels of cytokines (IL-1, IL-6, IL-8 or TNF) in humans Reducing down;

b) downregulating excessive in vivo levels of cytokines (IL-1, IL-6, IL-8 or TNF) in humans at the genome level or below the normal level;

c) downregulation by directly inhibiting the synthesis of cytokines (IL-1, IL-6, IL-8 or TNF) as a post-translational event; or

d) down-regulation of excessive in vivo levels of cytokines (IL-1, IL-6, IL-8 or TNF) in humans from translational levels to or below normal levels

Indicates.

As used herein, the term “TNF-mediated disease or disease state” refers to the TNF being reduced by the production of TNF itself or by release of other monokines derived from TNF, such as IL-1, IL-6 or IL-8. Any disease state that acts. Thus, for example, a disease state in which IL-1 is a major component and is secreted in response to TNF or worsens its production or action will be considered a disease state mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptide that affects the function of a cell, which is a molecule that modulates the interaction between cells in an immune, inflammatory or hematopoietic response. Cytokines include monocaine, lymphokine and the like regardless of the cells that produce them. For example, monocaine is generally shown to be produced and secreted by mononuclear cells, such as macrophages and / or monocytes. However, many other cells, such as natural killer cells, fibroblasts, basophilic leukocytes, neutrophils, endothelial cells, cerebral astrocytic cells, myeloid stromal cells, epidermal keratinocytes and B-lymphocytes also produce monokines. Lymphokines are generally shown to be produced by lymphocyte cells. Examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) and tumor necrosis factor-β (TNF- β), but is not limited to these.

As used herein, the term “cytokine inhibition” or “cytokine inhibition” refers to the normal in vivo levels of cytokines when administered to a patient for the prevention or treatment of a disease condition exacerbated or caused by the production of excessive or upregulated cytokines. The amount of the compound of formula (I) effective at reducing the level or below the normal level is indicated.

As used herein, the cytokines referred to in the phrase “inhibition of cytokines for use in the treatment of HIV-infected humans” include (a) T cell activation, and / or expression of activated T cell-mediated HIV genes and / or Initiation and / or maintenance of replication, and / or (b) cytokines associated with any cytokine-mediated disease related signs such as cachexia or muscle degeneration.

Because TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as capetine), because they each induce similar biological responses and bind to the same cellular receptors , TNF-α and TNF-β are both inhibited by the compounds of the present invention, so they are collectively referred to as "TNF" unless specifically stated otherwise herein.

Multiple MAP kinase families (also called CSBP, p38 or RK) have been individually identified in several laboratories. Activation of the novel protein kinase via dual phosphorylation when stimulated by a wide range of stimuli such as physicochemical stress and lipopolysaccharide or pro-inflammatory cytokines (eg interleukin-1 and tumor necrosis factor) in different cell lines Was observed. It has been determined that the cytokine biosynthesis inhibitors of the invention, compounds of formula I, are effective and selective inhibitors of CSBP / p38 / RK kinase activity. Some compounds of formula (I) have been shown to reversibly and time-dependently inhibit p38 kinase by the kinetics of slow binding and / or slow dissociation that result in improved apparent IC ₅₀ values when the compounds are preincubated with enzymes or cells. The slow, tight binding properties can contribute to the improved in vitro and in vivo efficacy of the compound.

These inhibitors help to determine signaling pathways associated with inflammatory responses. In particular, the first defined signal transduction pathway can be identified for the action of lipopolysaccharide in cytokine production in macrophages. In addition to the diseases already mentioned, stroke, neurotrauma, heart and kidney reperfusion injury, congestive heart failure, coronary artery bypass graft (CABG) surgery, chronic renal failure, angiogenesis and related processes such as cancer, thrombosis, glomerulonephritis, diabetes and pancreas Also included are treatments for β cells, multiple sclerosis, muscular degeneration, eczema, psoriasis, sunburn and conjunctivitis.

CSBP inhibitors were then tested for anti-inflammatory activity in a number of animal models. A model system was chosen that was relatively insensitive to cyclooxygenase inhibitors to reveal the unique activity of cytokine inhibitors. The inhibitor has shown significant activity in many of these in vivo studies. Most notable are the effects in the collagen-induced arthritis model and the inhibitory effect on TNF production in the toxic shock model. In a recent study, reduction in plasma levels of TNF is associated with survival and protection against endotoxin shock is associated with mortality. In addition, compounds that are effective in inhibiting bone resorption in a rat fetal iliac organ culture system are of great importance (Griswold et al., (1988) Arthritis Rheum. 31: 1406-1412; Badger, et al., ( 1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro.Bone 15, 533-538; Lee et al., (1993) .B Ann.NY Acad. Sci. 696, 149-170].

Chronic diseases that exhibit inadequate angiogenic factors are various ocular neovascularization symptoms such as diabetic retinopathy and decreased vision. Other chronic diseases with excessive or increased vascular amplification are tumor growth and metastasis, atherosclerosis, and certain arthritis symptoms. Thus, CSBP kinase inhibitors will be useful for blocking angiogenic components in such disease states.

The term “amplification of excessive or increased structurally inappropriate angiogenesis” as used herein includes, but is not limited to, diseases characterized by hemangiomas and ocular diseases.

As used herein, the term “inappropriate angiogenesis” includes, but is not limited to, a disease characterized by vesicle amplification involving tissue amplification resulting from cancer, metastasis, arthritis and atherosclerosis, for example.

Accordingly, the present invention comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal (preferably human) in need thereof for the treatment of a CSBP kinase mediated disease. Methods of treating kinase mediated diseases are provided.

Compounds of formula (I) or pharmaceutically acceptable salts thereof will typically be formulated into pharmaceutical compositions according to standard pharmaceutical practice for use in therapy. Accordingly, the present invention also relates to pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent that is not toxic.

The compounds of formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions incorporating them are conveniently administered by any route conventionally used for drug administration, eg, by oral, topical, parenteral or inhalation route of administration. Can be. The compound of formula (I) may be administered in a conventional dosage form prepared by combining the compound of formula (I) with a standard pharmaceutical carrier according to conventional procedures. The compounds of formula (I) can also be administered in conventional administration in combination with known second therapeutically active compounds. Such procedures may suitably include mixing, granulating and compacting or dissolving the ingredients in the desired formulation. It will be understood that the form and character of the pharmaceutically acceptable carrier or diluent will be determined by the amount of active ingredient to be mixed, the route of administration and other known variables. The carrier (s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not adversely affecting its recipients.

Pharmaceutical carriers used may be, for example, solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may comprise a time delay substance known in the art, such as glyceryl mono-stearate or glyceryl distearate, alone or in combination with wax.

A wide variety of pharmaceutical forms can be used. Thus, when a solid carrier is used, the preparation may be a tablet, inserted into a hard gelatin capsule in powder or pellet form, or in troki or lozenge form. The amount of solid carrier will vary widely but is preferably from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrups, emulsions, soft gelatin capsules, sterile injectable solutions such as ampoules or non-aqueous liquid suspensions.

The compound of formula (I) can be administered by topical route of administration, ie non-systemic route of administration. This includes applying a compound of formula (I) to the epidermis or outside the mouth and dropping the compound into the ears, eyes and nose, which prevents the compound from entering the bloodstream in significant amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin at the site of inflammation, such as linens, lotions, creams, ointments or pastes, and drops suitable for administration to the eyes, ears or nose. For topical administration, the active ingredient may be included at 0.001 to 10% w / w, such as 1 to 2% w / w, based on the weight of the formulation. However, it may be included up to 10% w / w, based on the weight of the formulation, preferably less than 5% w / w, more preferably 0.1 to 1% w / w.

Lotions in the present invention include those suitable for application to the skin or eyes. Eye drop lotions may optionally include sterile aqueous solutions containing fungicides, and may be prepared by methods similar to the method for preparing eye drops. Lotions or linings for application to the skin may also include substances that dry and cool the skin rapidly, such as alcohols or acetone, and / or wetting agents such as glycerol or oils such as castor oil or peanut oil.

Creams, ointments or pastes in the present invention are external semisolid formulations of the active ingredient. They may be prepared by mixing the active ingredient in finely divided form or in powder form, alone or in combination with an oily or non-oily base, with the aid of suitable means in an aqueous or non-aqueous solution or suspension. The base may be a hydrocarbon, such as hard, soft or liquid paraffin, glycerol, beeswax, metal soaps; mucus; Natural oils such as almond oil, corn oil, peanut oil, castor oil or olive oil; Wool or derivatives thereof, or fatty acids such as stearic acid or oleic acid may be included with alcohols such as propylene glycol or macrogels. The formulations may incorporate any suitable surface active agent such as anionic, cationic or nonionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural rubber, cellulose derivatives or inorganic materials such as silicatic silicon dioxide, and other components such as lanolin may also be included.

In the present invention, the eye drop may comprise a sterile aqueous solution, an oily solution or a suspension, and the active ingredient is dissolved in a suitable aqueous solution together with a fungicide and / or fungicide and / or any other suitable preservative, and preferably a surface active agent. It can manufacture. The resulting solution can then be clarified by filtration, transferred to a suitable container and sealed, which can be sterilized by autoclaving or left at 98-100 ° C. for 30 minutes. Alternatively, the solution can be sterilized by filtration and then transferred to the container using sterilization techniques. Examples of fungicides or fungicides suitable for inclusion in eye drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions are glycerol, dilute alcohol and propylene glycol.

The compounds of formula (I) can be administered by the parenteral route of administration, ie intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal or intraperitoneal. Among parenteral dosage forms, subcutaneous and intramuscular dosage forms are generally preferred. Appropriate dosage forms for such methods of administration may be prepared by conventional techniques. The compounds of formula I can also be administered by inhalation, i.e., intranasal and oral inhalation administration. Dosage forms suitable for such methods of administration, such as aerosol formulations and metered dose inhalers, can be prepared by conventional techniques.

In one embodiment of the invention, the formulation of the invention is delivered via oral inhalation or intranasal administration. Dosage forms suitable for such administration, such as aerosol formulations or metered dose inhalers, can be prepared by conventional techniques.

When administered by inhalation, the compound may be a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as tetrafluoroethane or heptafluoropropane, carbon dioxide Or other suitable gas may be used to deliver the aerosol spray appearance from the pressurized pack or sprayer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (eg of gelatin) used in an inhaler or insufflator containing a compound of the present invention and a suitable powder base (eg lactose or starch) can be formulated.

Dry powder compositions that are delivered locally to the lungs by inhalation may be present in capsules and cartridges (eg of gelatin) or blisters (eg of thin aluminum foil) used for example by inhalers or blowers. Powder blend formulations generally contain a powder mixture for inhalation of a compound of the invention and a suitable powder base group (carrier / diluent / excipient material) such as monosaccharides, disaccharides or polysaccharides (eg lactose or starch). Preference is given to using lactose.

Each capsule or cartridge may generally contain from 20 μg to 10 mg of a compound of Formula (I) or (Ia), optionally with other therapeutically active ingredients. Alternatively, the compounds of the present invention may be present without excipients.

Suitably, the packing / medicine dispenser is of a type selected from the group consisting of a storage dry powder inhaler (RDPI), a multidose dry powder inhaler (MDPI) and a metered dose inhaler (MDI).

Stored dry powder inhaler (RDPI) means an inhaler with a stored pack suitable for containing multiple (unmetered dose) drugs in dry powder form and including means for metering the drug dosage from the reservoir to the delivery site. do. The metering means may comprise, for example, a metering cup which is capable of moving from a reservoir to a second position from which a metered dose of medicine can be administered by inhalation to a patient from a first position where the drug can be filled into a cup.

Multidose dry powder inhaler (MDPI) means an inhaler suitable for dispensing a medicament in the form of a dry powder contained in a multidose pack containing (or otherwise transporting) a predetermined multidose (or portion thereof) of the drug. . In a preferred aspect, the carrier has the form of a blister pack, but it can also include the carrier applied to the medicament by any suitable process including, for example, capsule-based pack form or printing, painting and vacuum sealing.

For multidose delivery, the formulation may be pre-metered (e.g., Discus, (GB 2242134, US Pat. Nos. 6,632,666, 5,860,419, 5,873,360 and 5,590,645) or Diskhaler (GB 2178965, 2129691 and 2169265, US Pat. Nos. 4,778,054, 4,811,731, 5,035,237), the disclosures of which are incorporated herein by reference in their names, and may be quantified in use (e.g., Turbuhaler (see EP 69715) or in the United States) The device described in patent 6,321,747, the disclosure of which is incorporated herein by reference in its entirety).

The Discus suction device comprises a base sheet having a plurality of recesses spaced along its length section and an elongated strip formed from a cover sheet sealingly sealing it, preferably containing a compound of formula I or Ia, preferably with lactose. It defines a plurality of storage containers having a formulation for inhalation together. Preferably, the strip has sufficient solubility to wind up the roll. The cover sheet and the bottom sheet will preferably have guide ends that are not sealed to each other, and one or more of these guide ends are configured to attach to the winding device. Also, preferably the sealing seal between the bottom and the lid extends over their entire width. The cover sheet is preferably peelable from the bottom sheet in a vertical direction from the first end of the bottom sheet.

In one aspect, the multidose pack is a blister pack comprising several blisters for packaging a medicament in dry powder form. Blisters are typically aligned in a conventional manner that facilitates the release of medication from them.

In one aspect, the multidose blister pack comprises a plurality of blisters arranged in a general circular manner on a disc blister pack. In another aspect, the multidose blister pack is in an extended form that includes, for example, a strip or tape.

In one aspect, a multidose blister pack is defined between two members that are pillably fixed relative to each other. U.S. Patents 5,860,419, 5,873,360 and 5,590,645 describe such generic types of medicine packs. In this aspect, an opening is generally installed in the device that includes peeling means for peeling and separating members to approximate each medical dose. Suitably, the device is suitable for use where the peelable member is an extended sheet that defines a plurality of medication reservoirs spaced along its length section, the apparatus being equipped with indicator means for displaying each reservoir in turn. It is. More preferably, the device is suitable for use where any one of the sheets is a bottom sheet with multiple pockets and the other is a cover sheet, in which each pocket and a portion of the adjacent cover sheet has one storage container one by one. And driving means for pulling the cover sheet and the bottom sheet apart in the opening.

Metered dose inhaler (MDI) means a medication dispenser suitable for dispensing aerosol-type medication contained in an aerosol reservoir suitable for containing a propellant-based aerosol pharmaceutical formulation. Aerosol reservoirs are typically equipped with a metered valve, for example a slide valve, which releases the aerosol-type pharmaceutical formulation to the patient. Aerosol reservoirs are generally installed to deliver a predetermined dose of medication when actuated by a valve that can be pushed to open the reservoir if the reservoir is fixed or to open the reservoir if the valve is locked. It is.

When the medication reservoir is an aerosol reservoir, the valve typically controls the inlet through which the pharmaceutical aerosol formulation can enter the valve body, the outlet through which the aerosol can be discharged from the valve body, and the flow through the outlet. And a valve body having an opening and closing device.

The valve may be a slide valve in which the opening and closing device includes a valve tube having a closure ring and a distribution passage receivable by the closure ring, wherein the interior of the valve tube communicates with the exterior of the valve body by the distribution passage. Can slide in a loop from the valve-closed position to the valve-opened position.

Typically, the valve is a metering valve. The metered volume is typically 10-100 μl, such as 25 μl, 50 μl or 63 μl. Suitably, the valve body defines a metering chamber for metering the pharmaceutical formulation and an opening and closing device capable of controlling the flow into the metering chamber through the inlet. Preferably, the valve body has a sampling chamber in communication with the metering chamber through a second inlet, wherein the inlet can be controlled by an opening and closing device to regulate the flow of the pharmaceutical formulation entering the metering chamber.

The valve may also include a “free flow aerosol valve” having a chamber and a valve tube extending into the chamber and capable of moving into the chamber between the dispensing position and the non-dispensing position. The volume metered between each of them is defined and the valve tube sequentially enters (i) the free flow aerosol formulation into the chamber while traveling between the non-dispensing position and the dispensing position, and (ii) Define a closed metering volume for the pressurized aerosol formulation between the interior surfaces of the chamber, and (iii) the volume of the closed metering volume is dispensed until the metered volume communicates with the discharge passageway to dispense the metered volume of the pressurized aerosol formulation. It has a form and an inner form that allow it to move in a closed metered volume within the chamber without reducing it. Valves of this type are described in US Pat. No. 5,772,085. In addition, it is effective to deliver the compounds of the present invention intranasally.

In order to prepare an effective nasal pharmaceutical composition, the medicament must be readily delivered to all parts of the nasal cavity (target tissue) that perform its pharmacological function. In addition, the medicament should remain in contact with the target tissue for a relatively long time. If the medicament is kept in contact with the target tissue for a longer time, the medicament must be able to resist the forces acting to remove the particles from the nose in the nasal passages. This force (called 'mucociliary clearance') is known to be very effective in removing particles from the nose in a rapid manner, for example within 10 to 30 minutes from the time the particles enter the nose.

Another feature required for nasal compositions is that they should not contain ingredients that cause inconvenience to the user, have satisfactory stability and shelf life characteristics, and should not contain ingredients that are considered harmful to the environment, such as ozone depleting substances.

When administered to the nose, a suitable dosage regimen for the formulations of the present invention is to ensure that the nasal cavity is cleared after deep inhalation by the patient. During inhalation, the formulation will be applied to the other nostril while pressing one nostril by hand. This procedure is then repeated for the other nostril.

One means of applying the formulation of the present invention to nasal passages is to use a precompression pump. Most preferably, the precompression pump will be a VP7 model made by Valois SA. Such a pump may be beneficial because it does not release the formulation until sufficient force is applied unless a lower dosage can be applied. Another advantage of the precompression pump is that the spray injection does not release the formulation until the threshold pressure required for effective spray injection is reached. Typically, the VP7 model can use a bottle that can hold 10 to 50 ml of formulation. Each spray will typically deliver 50-100 μl of the formulation; Accordingly, the VP7 model can provide at least 100 metered doses.

Spray compositions that are delivered topically to the lungs by inhalation can be formulated, for example, in an aqueous solution or suspension, or in an aerosol delivered from a pressurized pack (such as a metered dose inhaler) using a suitable liquefied propellant. Aerosol compositions suitable for inhalation may be suspensions or solutions, and in general the compounds of formula (I) or formula (I ') may optionally contain other therapeutically active ingredients and suitable propellants such as fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof. In particular hydrofluoroalkanes such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, in particular 1,1,1,2-tetrafluoroethane, 1,1,1,2 , 3,3,3-heptafluoro-n-propane or mixtures thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may not include excipients and may optionally contain additional formulation excipients known in the art, such as surfactants such as oleic acid or lecithin, and cosolvents such as ethanol. The pressurized formulation is generally locked by a valve (eg metering valve) and will be contained in a canister (eg aluminum canister) installed in an actuator equipped with a mouthpiece. Medicines for inhalation administration preferably have a controlled particle size. The most suitable particle size for inhalation into the bronchial system is generally 1 to 10 μm, preferably 2 to 5 μm. Particles larger than 20 μm in size are generally too large to reach small airways when inhaled. To achieve this particle size, the particle size of the resulting active ingredient can be reduced by conventional means, for example by a micronization method. Desired fractions can be separated by air classification or using a sieve. Suitably the particles will be in crystalline form. If an excipient such as lactose is used, the particle size of the excipient will generally be much larger than the medication inhaled in the present invention. If the excipient is lactose, it will typically be present as ground lactose (up to 85% lactose particles will have an MMD of 60 to 90 μm and at least 15% of lactose particles will have an MMD of less than 15 μm).

Intranasal sprays can be formulated into aqueous or non-aqueous vehicles by adding agents such as thickeners, buffer salts, acids or alkalis (for pH adjustment), isotonicity modifiers or antioxidants.

Solutions for inhalation by nebulizers can be formulated into aqueous vehicles by the addition of agents such as acids or alkalis, buffer salts, isotonicity modifiers or antimicrobial agents. They may be sterilized by filtration or heated in an autoclave, or may be present as a non-sterile product.

Suitably, administration by inhalation preferably targets the target organ, ie lung, for respiratory disease, and may reduce the dose that needs to be delivered to the patient through such administration. In addition, administration by inhalation can reduce the exposure of the compound to the whole body, thereby preventing the compound from working anywhere else except in the lungs.

For all of the methods of use disclosed herein for the compounds of Formula I, the daily oral dosage is preferably about 0.05 to about 80 mg / kg, preferably about 0.1 to 30 mg / kg, based on total body weight, Preferably about 0.5 mg to 15 mg / kg, which is administered at least once daily. The daily parenteral dosage will be about 0.1 to about 80 mg / kg, preferably about 0.2 to about 30 mg / kg, more preferably about 0.5 to 15 mg / kg, based on total body weight, which is 1 daily. Administered more than once. The daily topical dosage will preferably be from 0.01 mg to 150 mg, which is administered 1 to 4 times daily. The daily inhalation dosage will be about 0.05 μg / kg to about 1 mg / kg, preferably about 0.2 to μg / kg to about 20 μg / kg, which is administered at least once daily. In addition, the person skilled in the art will determine the optimal amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the individual dose intervals will depend on the nature and extent of the condition being treated, the dosage form, the route and site, and the particular patient being treated and such an optimum It will be appreciated that the condition of can be determined by conventional techniques. Those skilled in the art will also understand that they may determine the optimal dosing regimen, i.e., the number of doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per day for a defined period of time using a conventional treatment decision test policy. .

The novel compounds of formula (I) can also be used in connection with veterinary treatment of non-human mammals in need of inhibition of CSBP / p38 or cytokine inhibition or production. In particular, therapeutically or prophylactically treating in animals CSBP / p38 mediated diseases include disease states, in particular viral infections, as mentioned in the Treatment Methods section herein. Examples of such viruses include lentiviral infections, such as equine infectious anemia virus, goat arthritis virus, visna virus or maedivirus, or retrovirus infections (eg feline immunodeficiency virus (FIV), bovine immunodeficiency virus or canine). Immunodeficiency virus, or other retroviral infections), but is not limited to these.

Another aspect of the invention requires the treatment of a common cold or respiratory virus infection caused by human linovirus (HRV), other enteroviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses or adenoviruses. A common cold, or human linovirus (HRV), other enterovirus, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adeno in said human, comprising administering to a human an effective amount of a CBSP / p38 inhibitor It is a method to treat respiratory viral infections caused by viruses.

Another aspect of the invention is a method of treatment including the prevention of influenza-derived pneumonia in a human comprising administering an effective amount of a CBSP / p38 inhibitor to a human being in need thereof for the treatment of influenza-derived pneumonia.

The invention also relates to CSBP / p38 kinase in the treatment including the prevention of inflammation associated with viral infection with human rhinovirus (HRV), other enteroviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses or adenoviruses. It relates to the use of an inhibitor.

In particular, the present invention relates to the treatment of viral infections caused by human linovirus (HRV), other enteroviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses or adenoviruses in humans. In particular, the present invention relates to respiratory viral infections that exacerbate asthma (derived by said infection), chronic bronchitis, chronic obstructive pulmonary disease, otitis media and sinusitis. While it may be known that inhibition of IL-8 or other cytokines may be beneficial for rhinovirus treatment, the use of inhibitors of p38 kinase in the treatment of HRV or other respiratory viral infections that cause a common cold is considered novel.

It should be noted that respiratory viral infections treated herein are also associated with secondary bacterial infections such as otitis media, sinusitis or pneumonia.

As used herein, treatment may include prophylaxis for use in treating a population susceptible to the infection. It may also include reducing the patient's symptoms, alleviating the symptoms, reducing the severity, reducing the incidence, or any other symptom change that improves the treatment outcome.

The treatment herein does not only directly remove or treat the viral organism itself but also exacerbate signs of other diseases or disorders such as asthma (derived by respiratory viral infection), chronic bronchitis, chronic obstructive pulmonary disease, otitis media and sinusitis. It should be noted that the treatment includes respiratory viral infections.

It is to be understood that the formulations of the present invention may include other formulations customary in the art, in particular in addition to the components mentioned above, depending on the type of formulation in question, for example, formulations suitable for oral administration may include flavoring agents. .

The compounds and pharmaceutical preparations according to the invention can be used for one or more other therapeutic agents, such as anti-inflammatory agents, anti-cholinergic agents (especially M ₁ , M ₂ , M ₁ / M ₂ or M ₃ receptor antagonists), β ₂ -adrenergic receptor efficacy Or may be used with or include an anti-infective agent (eg, an antibiotic, an antiviral agent) or a therapeutic agent selected from an antihistamine. Accordingly, the present invention further provides compounds of formula (I) or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof, such as anti-inflammatory agents (eg corticosteroids or NSAIDs), anticholinergic agents, β Combination is provided in combination with one or more other therapeutically active agents selected from _two -adrenergic agonists, anti-infectives (eg, antibiotics, antiviral agents) or antihistamines. One aspect of the invention is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof in combination with a corticosteroid and / or anti-cholinergic agent and / or a PDE-4 inhibitor. Preferred combinations are those comprising one or two different therapeutic agents.

Suitably the other therapeutic ingredient (s) may be salts (e.g., salts or acid addition salts of alkali metals or amines), prodrugs, esters (e.g. lower alkyl esters) or solvates (e.g. hydrates). It will be apparent to those skilled in the art that the present invention can be used in the form of) to optimize the activity and / or stability and / or physical characteristics (eg, solubility) of the therapeutic ingredient. It will also be apparent that the therapeutic ingredients may be suitably used in optically pure form.

One suitable combination of the invention comprises a compound of the invention in combination with a β ₂ -adrenergic receptor agonist.

Examples of β ₂ -adrenergic receptor agonists include salmeterol (which may be racemates or single enantiomers such as R-enantiomers), salbutamol, formoterol, salmephamol, phenoterol or terbutalin and Salts thereof, for example the cinafoate salt of salmeterol, the sulfate salt of salbutamol or the free base, the fumarate salt of formoterol. It is preferred to have a therapeutic effect for 24 hours, such as long-acting β ₂ -adrenergic receptor agonists, in particular salmeterol or formoterol.

Suitable long-acting β ₂ -adrenergic agonists are WO 02 / 66422A, WO 02/270490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 04 / 022547, WO 04/037807, WO 04/037773, WO 04/037768, WO 04/039762, WO 04/039766, WO 01/42193 and WO 03/042160, the disclosures of which are hereby incorporated by reference. Included as).

Preferred long-acting β ₂ -adrenergic receptor agonists

3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide ;

3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} amino) heptyl] oxy} propyl) benzenesulfonamide;

4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ;

4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol ;

N- [2-hydroxyl-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] Amino] ethyl] phenyl] formamide, and

N-2 {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5- (L) ethylamine.

Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids for use with the compounds of the present invention are oral and inhaled corticosteroids and their prodrugs that exhibit anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3- Oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- Androstar-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α -(1-Methylcyclopropylcarbonyl) oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy- 16α-methyl-3-oxo-17α- (2,2,3,3-tetramethylcyclopropylcarbonyl) oxy-androstar-1,4-diene-17β-carboxylic acid cyanomethyl ester, beclometha Hand esters (eg, 17-propionate ester or 17,21-dipropionate ester), budesonide, flunisolide, mometasone ester (eg furoate ester), tpyamcinolone acetonide, loflefonide, ciclesonide, (16α, 17- [ [(1R) -cyclohexylmethylene] bis (oxy)]-11β, 21-dihydroxy-pregna-1,4-diene-3,20-dione), butyxocoat propionate, RPR-106541 and There is ST-126. Preferred corticosteroids are flutacason propionate, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β -Hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, more preferably 6α, 9α-difluoro-17α-[(2 -Furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.

Non-steroidal compounds having selectivity for inhibition of metastasis rather than metastasis and having glucocorticoid action that may be useful in combination therapy are WO 03/082827, WO 01/10143, WO 98/54159, WO 04/005229, WO 04/009016, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651, WO 03/08277.

Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs).

Suitable NSAIDs include sodium chromoglycate, nedocromyl sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (eg , Montelukast), iNOS inhibitors, tryptase and elastase inhibitors, β ₂ integrin antagonists and adenosine receptor agonists or antagonists (eg adenosine 2a agonists), cytokine antagonists (eg chemokine antagonists such as CCR3 antagonists) or cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors. Other suitable β ₂ -adrenergic receptor agonists include salmeterol (eg in the form of cinafoate), salbutamol (eg in the form of sulfate or free base), formoterol (eg, Fumarate form), phenoterol or terbutalin and salts thereof. iNOS (inducible nitric oxide synthase inhibitor) is preferred for oral administration. Suitable iNOS inhibitors are those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors are those described in WO 02/26722.

Another embodiment of the invention is the use of a compound of formula (I) or formula (I ') in combination with a phosphodiesterase 4 (PDE4) inhibitor or a mixed PDE3 / PDE4 inhibitor. PDE4-specific inhibitors useful in this aspect of the invention may be any compound known to inhibit the PDE4 enzyme or found to act as a PDE4 inhibitor, and is intended to be a PDE4 inhibitor and may not only contain PDE4 but also other PDE family members. Inhibiting compounds are not included. Generally, the roll is preferred to use a leaf person degree PDE4 IC ₅₀ a roll leaf alarm IC ₅₀ ratio of about 0.1 or more PDE4 inhibitor divided by the IC ₅₀ for the form which combines the road low affinity to about catalytic form that binds to repairing the . For the purposes of the present disclosure, cAMP catalyst sites that bind to R and S rolipram with low affinity are termed "low affinity" binding sites (LPDE 4), and other forms of the above that bind to rolipram with high affinity. The catalytic site is named "high affinity" binding site (HPDE 4). The term "HPDE4" should not be confused with the term "hPDE4" used to refer to human PDE4.

Methods of determining IC ₅₀ are described in US Pat. No. 5,998,428 (incorporated herein as incorporated herein by reference in its entirety). See also PCT application WO 00/51599 for another description of this analysis. In one embodiment, the PDE4 inhibitors used in the present invention have a high affinity for apparently high affinity for rolipram by preferentially inhibiting cAMP catalytic activity, a compound that exhibits a beneficial therapeutic rate, i.e., a form in which the enzyme binds low-affinity to rolipram. Compounds that reduce the side effects associated with inhibition of the binding form. In other words, it is greater than IC ₅₀ ratio of about 0.1 the compound divided by the IC ₅₀ for the form which combines the road that the affinity IC ₅₀ in roll leaf person for PDE4 catalytic form that binds to a degree of repairing a roll leaf person.

Further specifying this criterion, the compounds used in the present invention are PDE4 inhibitors having an IC ₅₀ ratio of at least about 0.1, which ratio binds low-affinity to lolliram using 1 μM [ ³ H] -cAMP as a substrate. the form of the IC ₅₀ value for competing with the binding when in the form of 1 nM ^[3 H] R- roll leaf person to PDE4 combined in the degree of PDE4 repairing a roll leaf farm for the IC ₅₀ value in the case of inhibiting the catalytic activity It is rain.

Suitable PDE compounds are cis 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3- Cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1 -All]; These are examples of compounds which preferentially bind to low affinity binding sites and have an IC ₅₀ ratio of at least 0.1.

Other compounds of interest include those listed in US Pat. No. 5,552,438 (September 3, 1996; the above and particularly compounds disclosed herein are incorporated herein by reference in their entirety). Of particular interest are compounds disclosed in US Pat. No. 5,552,438, ie cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid (also, silomala Straw) and salts, esters, prodrugs or natural forms thereof; AWD-12-281 (elbion) (see Hofgen, N. et al. 15th EFMC Int. Symp. Med. Chem. (Sept 6-10, Edinburgh) 1998, Abst. P. 98); CAS Number 247584020-9); 9-benzyladenin derivatives (registered as NCS-613) (INSERM); D-4418 (Chiroscience and Schering-Plough); Benzodiazepine PDE4 inhibitor (designated CI-1018) (PD-168787) (owned by Pfizer); Benzodioxol derivatives (disclosed in WO 99/16766 to Kyowa Hakko); K-34 (Kyo and Hako); V-11294A (Napp; Napp) (Landells, LJ. Et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393) ; Loflumilast (CAS Ref. No. 162401-32-3) and phthalazinone (WO 99/47505, the disclosure of which is incorporated herein by reference) (Bik-Gulden); Fumapentrin, (-)-p-[(4αR *, 10bS *)-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [c ] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide (mixed PDE3 / PDE4 inhibitors prepared and published by Vik-Gilden (now Altana)); Arophylline (developed by Almirall-Prodesfarma); VM554 / UM565 (Vernalis); Or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162), and T2585. Other possible PDE4 and mixed PDE3 / PDE4 inhibitors include those listed in WO 01/13953, the disclosure of which is incorporated herein by reference in its name.

Suitable anticholinergic agents are compounds which act as antagonists at muscarinic receptors, in particular antagonist compounds of the M1 and M2 receptors. Exemplary compounds include belladonna plant alkaloids, which are described as atropine, scopolamine, homatropin, hydroxysamine, and the like, which are typically administered as salts (tertiary amines). Such drugs, in particular salt forms, are readily available from a number of commercial sources or may be prepared or prepared from literature data:

Atropine-CAS-51-55-8 or -CAS-51-48-1 (anhydrous form), atropine sulfate -CAS-5908-99-6; Atropine oxide -CAS-4438-22-6 or its HCl salt -CAS-4574-60-1 and methylatropine nitrate -CAS-52-88-0; Homatropin-CAS-87-00-3, hydrobromide salt-CAS-51-56-9, methylbromide salt-CAS-80-49-9; Biosciamine (d, l) -CAS-101-31-5, hydrobromide salt -CAS-306-03-6 and sulphate salt -CAS-6835-16-1; And scopolamine-CAS-51-34-3, hydrobromide salts-CAS-6533-68-2, methylbromide salts-CAS-155-41-9.

Anti-cholinergic agents suitable for use in the present invention include ifpratropium (eg, in the form of bromide, cifamci under the trade name Atrovent), oxytrolium (eg, in the form of bromide), and Tiotropium (eg in the form of bromide) (CAS-139404-48-1), but is not limited to these. In addition, the agents of interest are methanetellin (CAS-53-46-3), propanetelin bromide (CAS-50-34-9), anisotropin methyl bromide or Valpin 50 (CAS-80-50- 2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul; Robinul), isopropamide iodide (CAS-71-81-8), meth Phenzolate bromide (US Pat. No. 2,918,408), tridihexetyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9) to be. In addition, cyclopentolate hydrochloride (CAS-5870-29-1), trophamide (CAS-1508-75-4), trihexhenidyl hydrochloride (CAS-144-11-6), pyrenzepine ( CAS-29868-97-1), tellenezepine (CAS-80880-90-9), AF-DX 116 or methotramine, and WO 01/04118 (the disclosures of which are incorporated herein by reference through this name) See the compounds disclosed in).

Other suitable anticholinergic agents include compounds of formula XXI (disclosed in US patent application 60/487981).

Where

The preferred orientation of the alkyl chain attached to the tropan ring is endo;

R ³¹ and R ³² are preferably straight or branched chain lower alkyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2- Thienyl, 2-pyridyl, phenyl, phenyl substituted with alkyl groups having up to 4 carbon atoms and phenyl substituted with alkoxy groups having up to 4 carbon atoms;

X "represents an anion connected with the positive charge of N atom.

X "may be chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate, for example

(3-endo) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane4-methylbenzenesulfonate;

(3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide; And / or

(3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide.

Further suitable anti-cholinergic agents include compounds of the formula XXII or XXIII (disclosed in US patent application 60/511009).

Where

The indicated H atom is at the exo position;

R ⁴¹ represents an anion linked to the positive charge of the N atom, which may be chloride, broamide, iodide, sulfate, benzene sulfonate, toluene sulfonate, or the like;

R ⁴² and R ⁴³ are straight or branched chain lower alkyl groups (preferably having 1 to 6 carbon atoms), cycloalkyl groups (having 5 to 6 carbon atoms), cycloalkyl-alkyl (s 6 to 10 carbon atoms) ), Heterocycloalkyl (with 5 or 6 carbon atoms and N or O as heteroatom), heterocycloalkylalkyl (with 6 or 10 carbon atoms and N or O as heteroatom), aryl, optionally Independently selected from the group consisting of substituted aryl, heteroaryl and optionally substituted heteroaryl;

R ⁴⁴ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl, -OR ⁴⁵ , -CH ₂ OR ⁴⁵ , -CH ₂ OH, -CN, -CF ₃ , -CH ₂ O (CO) R ⁴⁶ , -CO ₂ R ⁴⁷ , -CH ₂ NH ₂ , -CH ₂ N (R ⁴⁷ ) SO ₂ R ⁴⁵ , -SO ₂ N (R ⁴⁷ ) (R ⁴⁸ ), -CON (R ⁴⁷ ) (R ⁴⁸ ), -CH ₂ N (R ⁴⁸ ) CO (R ⁴⁶ ), -CH ₂ N (R ⁴⁸ ) SO ₂ (R ⁴⁶ ), —CH ₂ N (R ⁴⁸ ) CO ₂ (R ⁴⁵ ), —CH ₂ N (R ⁴⁸ ) CONH (R ⁴⁷ );

R ⁴⁵ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, ( C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl;

R ⁴⁶ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , A group consisting of (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl Is selected from;

R ⁴⁷ and R ⁴⁸ are H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C _3- C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl-aryl and (C ₁ -C ₆ ) alkyl-heteroaryl Independently from.

Representative examples

(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile;

(Endo) -8-methyl-3- (2,2,2-triphenyl-ethyl) -8-aza-bicyclo [3.2.1] octane;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propan-1-ol;

N-benzyl-3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;

(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

1-benzyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

1-ethyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide;

3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile;

(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide;

[3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -methanesulfonamide; And / or

(Endo) -3- {2,2-diphenyl-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] Octane bromide.

Preferred compounds useful in the present invention include

(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;

(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;

(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide ; And / or

(Endo) -3- {2,2-diphenyl-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] Octane bromide.

Suitable antihistamines (also referred to as H ₁ -receptor antagonists) inhibit H ₁ -receptors and include one or more of a number of antagonists known to be safe for human use. These are all reversible competition inhibitors of the interaction of histamine with H ₁ -receptors. Most of these inhibitors (mostly first generation antagonists) have a core structure which can be represented by the formula:

The generalized structural formulas generally represent three types of antihistamines available: ethanolamine, ethylenediamine and alkylamine. In addition, other first generation antihistamines include those that can be characterized based on piperizine and phenothiazine. Second generation antagonists (which are non-tranquilizers) exhibit similar structure-activity relationships in that they possess a core ethylene group (alkylamine) or similar tertiary amine groups (including piperizine or piperidine). Examples of antagonists include:

Ethanolamine: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride and dimenhydrinate.

Ethylenediamine: pyrylamine maleate, tripelennamin HCl and tripelennamin citrate.

Alkylamines: chloropheniramine and salts thereof such as maleate salts, and acrivastin.

Piperazine: hydroxyzin HCl, hydroxyzin pamoate, cyclizin HCl, cyclizin lactate, meclizin HCl and cetirizine HCl.

Piperidine: Astemizol, levocarvastin HCl, loratadine or decarboethoxy analogs thereof, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is another H ₁ receptor antagonist that can be used in combination with PDE4 inhibitors.

The abovementioned combinations may conveniently be present for use in the form of pharmaceutical preparations, whereby pharmaceutical preparations comprising the above defined combinations with physiologically acceptable diluents or carriers represent a further aspect of the invention.

The individual compounds that make up the combination can be administered sequentially or simultaneously in separate and combined pharmaceutical formulations. Appropriate dosages of known therapeutic agents will be readily apparent to those skilled in the art.

The invention will now be described with reference to the following biological examples, which are for illustrative purposes only and are not to be considered as limiting the scope of the invention.

Biological Example

Cytokine-inhibitory effects of the compounds of the invention can be determined by in vitro assays as follows.

Assays for interleukin-1 (IL-1β), interleukin-8 (IL-8), and tumor necrosis factor (TNFα) are well known in the art and can be found in numerous publications and patent literature. Representative assays suitable for use in the present invention are described in US Pat. No. 5,593,992 to Adams et al., The disclosure of which is incorporated herein by reference in its entirety.

It is appreciated that each assay in the present invention can be performed multiple times for certain compounds such as Formula I or Ia described herein. As reported in these assays, activity measurements will be based on their mean or median value.

Interleukin-1 ( IL -One)

Human peripheral blood mononuclear cells are isolated and the procedure of Colotta et al., J Immunol, 132, 936 (1984) or MACS CD 14+ beads is isolated from fresh blood preparations obtained from volunteer donors or smoke screens of blood banks. Purification was carried out according to other suitable procedures such as the positive screening method used. These monocytes (1 × 10 ⁶ ) were plated in 24, 48, 96 or 384-well plates at a concentration of 1 × 10 ⁶ to 2 × 10 ⁶ cells / ml per well. The cells were allowed to attach for 2 hours, after which the unattached cells can be gently washed off. The test compound was then added to the cells for 1 hour followed by lipopolysaccharide (50-200 ng / ml) and the culture was further incubated at 37 ° C. for 24 hours. At the end of the incubation, the culture supernatant was removed and the cells and all cell debris were removed. IL-1β levels in cell-free supernatants were then measured by enzyme-linked immunoassay (ELISA) or other antibody-based procedures.

In vivo TNF  analysis:

(1) Griswold et al, Drugs Under Exp, and Clinical Res., XIX (6), 243-248 (1993); or

(2) Boehm, et al, Journal Of Medicinal Chemistry 39, 3929-3937 (1996)

(These disclosures are incorporated herein by reference in their entirety).

Mouse and In rats LPS -Induced TNF generation of α

To assess in vivo inhibition of production of LPS-induced TNFα in rodents, both mice or rats were injected with LPS.

Mouse way

Male Balb / c mice obtained from Charles River Laboratories were pretreated (30 min) with compound or vehicle. After pretreatment for 30 minutes, mice received LPS ( E. coli ) serotype 055-B5 (Sigma Chemical Co .; Missouri, USA) in 25 μl of phosphate buffered saline (pH 7.0). Lipopolysaccharide) from St. Louis) was injected intraperitoneally at 25 μg / mouse. After 2 hours the mice were euthanized by CO ₂ inhalation, blood was collected and blood samples collected in heparised blood collection tubes and stored on ice. Blood samples were centrifuged, plasma collected and stored at −20 ° C. until analyzed for TNFα by ELISA.

Rat  Way

Male Lewis rats obtained from Charles River Laboratories were pretreated with compound or vehicle several times. After a predetermined pretreatment time, rats were injected intraperitoneally with 3.0 mg / kg of LPS (lipopolysaccharide obtained from E. coli serotype 055-B5 (Sigma Chemical, St. Louis, MO)). Rats were euthanized by CO ₂ inhalation 90 minutes after LPS injection and heparinized whole blood was collected from each rat by cardiac puncture. Blood samples were centrifuged and plasma was collected and used for analysis of TNFα levels by ELISA.

ELISA  Way

TNFα levels were obtained using hamster monoclonal anti-murine TNFα (Genzyme, Boston, Mass.) As the capture body and polyclonal rabbit anti-murine TNFα (Genzyme) as the second antibody. Sandwich ELISA (Olivera et al., Circ.Shock, 37, 301-306, (1992), the disclosure of which is incorporated herein by reference in its entirety). To detect, 1 mg / ml substrate for peroxidase (1% urea peroxide) after addition of peroxidase-conjugated goat anti-rabbit antibody (Pierce, Rockford, Ill.) Orthophenylenediamine) was added. TNFα levels in plasma obtained from each animal were calculated from standard curves generated using recombinant murine TNFα (genzyme).

human In whole blood LPS Stimulated Cytokine  produce

Assay : Test compound concentrations were prepared at 10 × concentrations, LPS was prepared at 1 μg / ml (final concentration 50 ng / ml LPS) and added to 1.5 mL eppendorf tubes in 50 μl volume. Heparinized whole blood was obtained from healthy volunteers and dispersed in eppendorf tubes or multiwell plates containing 0.2-0.4 mL volume of compound and LPS and the tubes were incubated at 37 ° C. In some studies, LPS was added after compound was incubated with blood for up to 30 minutes. After incubation for 4 hours, the tubes or plates were centrifuged to remove cells and the plasma collected and frozen at -80 ° C.

Cytokine Determination : IL-1β and / or TNFα were quantified using standardized ELISA or similar techniques. Concentrations of IL-1β or TNFα were determined from standard curves of appropriate cytokines and IC ₅₀ values (concentrations that inhibit 50% production of LPS-stimulated cytokines) for test compounds were calculated by linear regression analysis.

result

In the assay, compounds that were proven to be less than 10 μM and had IC ₅₀ values of less than about 0.0001 μM were considered active.

Examples 3, 4, 21 (c), 22, 24, 25, 27, 29, 30, 31 (e), 32, 35, 37 (b), 38, 40, 44, 46, 47, 54, 56 Representative Formulas I and Ia described in (d), 57-66, 68-78, 79 (c), 82, 87, 99, 101-105, 107, 109, 118 (b), 122-125, 128 and 129 The compounds of were tested in the above assay and were found to be active.

The compounds of Examples 93, 97 (b) and 100 were found to have IC ₅₀ values above 0.1 μM in this assay. These compounds have been shown to inhibit the production of TNF-α by more than 50% at 1 μM, but some of them are expected to achieve 50% inhibition when tested again at increased concentrations.

CSBP Of p38 Kinase  analysis:

The assay measures CSBP / p38-catalyzed migration from [a- ³² P] ATP to threonine residues in epidermal growth factor receptor (EGFR) -derived peptide (T669) having the sequence KRELVEPLTPSGEAPNQALLR (residues 661-681). (See Gallagher et al., "Regulation of Stress Induced Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSBP Kinase", BioOrganic & Medicinal Chemistry, 1997, 5, 49-64).

The reaction was carried out in a 30 ml volume round bottom 96 well plate (Corning). The reaction was 25 mM Hepes (pH 7.5); 8 mM MgCl ₂ ; 0.17 mM ATP (see p 38 Km _{[ ATP ]} ; Lee et al., Nature 300, n72 pg. 639-746 (Dec. 1994)); 2.5 μCi of [g-32P] ATP; 0.2 mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669 peptide; And 2 to 4 nM yeast-expressed, activated and purified p38 (final concentration). The reaction was initiated by addition of [γ-32P] Mg / ATP and incubated at 37 ° C. for 25 minutes. The inhibitor (dissolved in DMSO) was incubated with the reaction mixture on ice for 30 minutes before 32P-ATP was added. Final DMSO concentration was 0.16%. The reaction was terminated by the addition of 10 μl 0.3 M phosphoric acid and isolated from the reaction by trapping phosphorylated peptide on a p81 phosphocellulose filter. The filter was washed with 75 mM phosphoric acid and the introduced 32P was quantified using a β scintillation counter. Under these conditions, the specific activity of p38 was 400-450 pmol / pmol (enzyme) and the activity increased (proportionally) during incubation up to 2 hours. Kinase activity levels were obtained after subtracting the resulting values (values of 10-15% total) in the absence of a substrate.

Neon Anisotropy Kinase  Binding Analysis-Standard Volume

Kinase enzymes, fluorescent ligands, and test compounds of varying concentrations are incubated together such that in the absence of the test compound the fluorescent ligand binds to a significant amount (greater than 50%) enzyme and in the presence of a sufficient concentration (greater than 10 × Kj) of an effective inhibitor. Thermodynamic equilibrium was achieved under conditions that differed measurably from the values when anisotropy of unfluorescent fluorescent ligands were bound.

The concentration of the kinase enzyme should preferably be at least 2 × Kf. The concentration of fluorescent ligand required will vary depending on the means used and the fluorescence and physicochemical properties. The concentration used should be lower than the concentration of the kinase enzyme, preferably less than half the concentration of the kinase enzyme.

Fluorescent ligands are compounds (5- [2- (4-aminomethylphenyl) -5-pyridin-4-yl-1H-imidazol-4-yl] -2-chlorophenol and derived from rhodamine green).

Recombinant human p38α was expressed with GST-tagged protein. To activate the protein, 3.5 μM inactivated p38α was purified by 50 mM Tris-HCl (pH 7.5), 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodium vanadate, 10 mM MgAc, 0.1 mM ATP ( Incubated at 30 ° C. for 30 minutes in 200 nM MBP-MKK6 DD). After activating p38α it was purified again and activity was assessed using standard filter-binding assays.

Protocol: All components were dissolved in buffer with a composition of 62.5 mM HEPES (pH 7.5), 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl ₂ , so that the final concentrations of p38α and fluorescent ligand were 12 nM and 5 nM, respectively. Add 30 μl of the reaction mixture to a well containing 1 μl of various concentrations of test compound (final 0.28 nM to 16.6 μM) or DMSO vehicle (final 3%) in a NUNC 384 well black microtight plate and add 30 to 60 minutes at room temperature. Equilibrate for Fluorescence anisotropy was read at Molecular Devices Acquest (excitation 485 nm / emission 535 nm).

Justice

Ki = dissociation constant for inhibitor binding

Kf = dissociation constant for fluorescent ligand binding

Neon Anisotropy Kinase  Combination Low volume  analysis

Kinase enzymes, fluorescent ligands, and test compounds of varying concentrations are incubated together such that in the absence of the test compound the fluorescent ligand binds to a significant amount (greater than 50%) enzyme and in the presence of a sufficient concentration (greater than 10 × Kj) of an effective inhibitor. Thermodynamic equilibrium was achieved under conditions that differed measurably from the values when anisotropy of unfluorescent fluorescent ligands were bound.

The concentration of the kinase enzyme should preferably be 2 × Kf. The concentration of fluorescent ligand required will vary depending on the means used and the fluorescence and physicochemical properties. The concentration used should be lower than the concentration of the kinase enzyme, preferably less than half the concentration of the kinase enzyme.

Fluorescent ligands are compounds (5- [2- (4-aminomethylphenyl) -5-pyridin-4-yl-1H-imidazol-4-yl] -2-chlorophenol and derived from rhodamine green).

Recombinant human p38α was expressed with GST-tagged protein. To activate the protein, 3.5 μM inactivated p38α was purified by 50 mM Tris-HCl (pH 7.5), 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodium vanadate, 10 mM MgAc, 0.1 mM ATP ( Incubated at 30 ° C. for 30 minutes in 200 nM MBP-MKK6 DD). After activating p38α it was purified again and activity was assessed using standard filter-binding assays.

Protocol: All components were dissolved in buffer with a composition of 62.5 mM HEPES (pH 7.5), 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl ₂ , so that the final concentrations of p38α and fluorescent ligand were 12 nM and 5 nM, respectively. 30 μl of the reaction mixture is added to a well containing 0.1 μl of various concentrations of test compound (final 0.02 nM to 25 μM) or DMSO vehicle (final 1.7%) in a Greiner low volume 384 well black microtight plate, Equilibrate at room temperature for 30-60 minutes. Fluorescence anisotropy was read at Molecular Devices Acquest (excitation 485 nm / emission 535 nm).

Justice

Ki = dissociation constant for inhibitor binding

Kf = dissociation constant for fluorescent ligand binding

Note that there are two assay formats described above for fluorescence anisotropic kinase binding assays. The only difference between the two assays is the volume and plate type used. There was no difference in the efficacy of the two formats, and therefore these assays were considered equivalent. The results described herein can be performed in one of the two analysis formats, and are not shown differently.

result

In the assay, compounds that proved to be active were above 4.6 and had a pIC ₅₀ value of up to about 9.0.

Example 1 (d), 2 (b), 3 to 6, 7 (c), 7 (d), 8, 11, 12c, 13, 17, 18e, 19 (a), 19 (c), 20, 21 (a), 21 (c), 22 to 30, 31 (e), 32, 34, 35, 36, 37a, 37b, 38 to 55, 56 (d), 57 to 61 to 78, 79 (c) , 80 (a), 80 (b), 81-95, 97 (b), 98-112, 113 (b), 114 (b), 115, 116 (b), 116 (c), 117, 118 ( Representative compounds of Formulas (I) and (Ia) described in a), 118 (b), 119-121 and 202 (c) were tested in the above assays, and they were demonstrated to have pIC ₅₀ values ranging from 5.1 to 8.4.

The compounds of 1 (a), Example 9, Example 96 (d) and Example 114 (b) did not demonstrate in this assay to show a pIC ₅₀ value of less than 4.8 at concentrations below 16 μM.

TR - FRET  analysis

Time-resolved Fluorescence Resonance Energy Transfer Kinase  Standard analysis

Recombinant human p38α was expressed with His-tagged protein. To activate the protein, 3 μM inactivated p38α was added at 200 mM Hepes (pH 7.4), 625 mM NaCl, 1 mM DTT (27 nM active MKK6 (Upstate), 1 mM ATP and 10 mM MgCl ₂ . Incubation The activity of MKK6-activated p38α was assessed using time-resolved fluorescence resonance energy transfer (TR-FRET) analysis.

Biotinylated-GST-ATF2 (residues 19-96, final 400 nM), ATP (final 125M) and MgCl ₂ (final 5 mM) in NUNC in assay buffer (40 mM HEPES (pH 7.4), 1 mM DTT) 384 well black plates were added to wells containing 1 μl of various concentrations of compound or DMSO vehicle (final 3%). The reaction was initiated by the addition of MKK6-activated p38 (final 100 pM) to bring the total volume to 30 μl. The reaction was incubated at room temperature for 120 minutes before the reaction was terminated by the addition of 15 μl of 100 mM EDTA (pH 7.4). Antiphosphothreonine-ATF2-71 polyclonal antibody (Cell Signaling Technology, Beverly, Mass.) Labeled with W-1024 europium chelate (Wallac OY, Turku, Finland) and APC In buffer containing labeled streptavidin (Prozyme, San Lindo, Calif.) (100 mM HEPES, pH 7.4), 150 mM NaCl, 0.1% w / v BSA, 1 mM DTT Detection reagent (15 μl) was added and the reaction was incubated another 60 minutes at room temperature. Phosphorylation of GST-ATF2 was determined using a Packard Discovery plate reader (Perkin-Elmer Life Sciences, Pangborn, UK), specific 665 nm energy for a reference Europium 620 nm signal. It was measured by the ratio of the moving signal.

Time-resolved Fluorescence Resonance Energy Transfer Kinase Low volume  analysis

Recombinant human p38α was expressed with His-tagged protein. To activate the protein, 3 μM inactivated p38α was incubated in 200 mM Hepes, pH 7.4, 625 mM NaCl, 1 mM DTT (27 nM active MKK6 (Upstate), 1 mM ATP, and 10 mM MgCl ₂ . The activity of MKK6-activated p38α was assessed using time-resolved fluorescence resonance energy transfer (TR-FRET) analysis.

Biotinylated-GST-ATF2 (residues 19-96, final 40 nM), ATP (125 μM final) and MgCl ₂ (final 5 mM) in assay buffer (40 mM HEPES, pH 7.4, 1 mM DTT) Liner low volume 384 well black plates were added to wells containing 0.1 μl of various concentrations of compound or DMSO vehicle (final 1.7%). MKK6-activated p38 (final 100 pM) was added to initiate the reaction to bring the total volume to 6 μl. After incubating the reaction at room temperature for 120 minutes, antiphosphothreonine-ATF2-71 polyclonal antibody (Cell Signaling Technology, Beverly, Mass.) Labeled with W-1024 europium chelate (Balak OY, Turku, Finland) ) And buffer containing APC-labeled streptavidin (Prozyme, San Lindo, CA, USA) (100 mM HEPES, pH 7.4), 150 mM NaCl, 0.1 weight / volume BSA, 1 mM DTT, The reaction was terminated by adding 3 μl of detection reagent in 100 mM EDTA). The reaction was incubated another 60 minutes at room temperature. The degree of phosphorylation of GST-ATF2 was measured using a BMG Rubystar plate reader (BMG, UK) as the ratio of the specific 665 nm energy transfer signal to the reference Europium 620 nm signal.

Note that there are two assay formats described above for time-divided fluorescence resonance energy transfer kinase binding assays. The only difference between the two assays is the volume and plate type used. There was no difference in the efficacy of the two formats, and therefore these assays were considered equivalent. The results described herein can be performed in one of the two analysis formats, and are not shown differently.

result

In the assay, compounds that were proven to have pIC ₅₀ values in the range above 4.6 and above about 10.0 were considered active.

Representative compounds of Formulas (I) and (Ia) were tested in this assay, and Examples 9, 10, 15, 18 (e), 31 (e), 34, 36, 56 (d), 57, 60-62, 66, 74 , 78, 79 (c), 98-107, 109, 112, 113 (b), 114 (b), 117, 118 (a), 118 (b), 119-149, 150 (d), 151-156 , 158 to 160, 162, 163 (b), 163 (c), 164 to 178, 179 (b), 179 (c), 180 to 187, 188 (b), 189 to 192, 193 (a), 193 (b), the compounds described in 194 to 201 were shown to be active in this assay.

The compounds of Example 97 (b) and Example 115 showed extensive data ranging from 7.4 to less than 4.6 of the pIC ₅₀ value as a result of performing the assay several times. The compound of Example 188 (a) did not prove in this assay to show a pIC ₅₀ value of less than 4.8 at a concentration of less than 16 μM.

HTRF assay and fluorescence anisotropic kinase binding assay used for the purposes of the present invention:

From human neutrophils TNF Stimulated IL Generation of -8

The effect of the test compound on the production of TNF-stimulated IL-8 by human neutrophils was determined as follows. Neutrophils were prepared using standard methods from blood obtained from agreed donors. Blood was collected in a heparinized syringe and stacked on histopaque (30 ml / 20 ml). After centrifugation, the red blood cell pellet was resuspended in PBS and purified on a dextran gradient. Erythrocyte cells were lysed with water for 40 seconds and the remaining granulocytes were collected by centrifugation and suspended again at 1.5 × 10 ⁶ cells / ml. Cells (0.5-1 ml) were added to 48 well plates already containing 1000X final concentration of compound in either pure DMSO or 10% DMSO in RPMI1640 with 10% FBS. TNF (final concentration 100 ng / ml) was used as a stimulant. Cells were incubated at 37 ° C., 5% CO ₂ for approximately 20 hours. The level of IL-8 in cell-free supernatants was measured by sandwich ELISA and the degree of inhibition compared to the control group containing DMPO and no compound was calculated.

result

The assay proved to have an IC ₅₀ value of less than 10 μM and less than about 0.0001 μM and considered compounds active at concentrations up to 100 nM.

Example 2 (b), 3, 5, 6, 8, 13, 18 (e), 21 (c), 22 to 26, 28 to 30, 31 (e), 32 to 36, 37 (a) and ( b), 38 to 47, 54, 56 (d), 57 to 66, 68 to 78, 79 (c), 80 (b), 81 to 85, 87, 95, 99 to 105, 107, 109, 112, 113 (b), 114 (b), 115, 117, 118 (b), 119, 122-129, 132-145, 147-149, 150 (d), 151, 158-160, 162, 163 (c) Representative compounds of Formulas (I) and (Ia) described in 164 to 170, 172 to 178, 179 (c), 180 to 187, 193 (b) and 194 to 201 were tested in the above assays and were found to be active.

Examples 1 (a), 7 (c) and (d), 9-11, 12 (c), 14 (c), 15-17, 51-53, 80 (a), 110, 111, 116 (b ), 118 (a), 146, 152 to 157, 163 (b), 171, 170 (b), 188 (a) and (b), 193 (a), 189 and 191 to 192 are compounds It has been proven to have IC ₅₀ values above 0.1 μM. The compounds of Examples 130 and 131 were found to have IC ₅₀ values of greater than 0.01 μM in this assay. The compound of Example 190 was proved to have an IC ₅₀ value of greater than 0.03 μM in this assay. These compounds mentioned later were screened at the highest concentrations other than in the above classification. These compounds did not appear to inhibit the production of IL-8 by more than 50% at 100 nM, but some of them are expected to achieve 50% inhibition when tested again at increased concentrations.

The compound of Example 202 (c) showed extensive IC ₅₀ data in the range of more than 0.01 μM to more than 0.1 μM as a result of performing the above assay several times. The compound of Example 120 was subjected to a number of IC ₅₀ assays ranging from greater than 0.001 μM to greater than 0.1 μM. Data is shown.

Rat LPS  Neutrophil model

The effect of the compound on neutrophil influx into the lungs of LPS-immunized rats was evaluated as follows. Test compounds were prepared with 0.5% tween 80 / PBS, 0.5% tween 80 / saline, 10% EtOH / saline (with or without pH adjusted to 2.0 or 8.0), brine @ (pH 2.0, 6.5 or 8.0), Suspended in a solution of either 0.5% tragacanth, 1% DMSO / 20% Encapsin / saline, or acidified 5% tragacanth. A glass homogenizer can be used to assist in the suspension process. When administered intratracheally, anesthetize the animal by isoflurane inhalation and lay it flat, and place a tracheal gavage needle (1.5 inch, 22 gauge, small ball) or Pen-Century Microsprayer Aerosolizer on the trachea. ) (Model IA-IB) was intubated to deliver 200 μl of dosing solution. Animals were visually monitored during the recovery process, which typically occurs within 2 minutes. Note that the test compound may be administered differently via microinjector in a dry powder blend with a suitable excipient such as lactose.

Rats treated with compound or vehicle (15 min-24 h pretreatment) were exposed to LPS aerosol (100 μg / ml) for 15 min. After 4 hours, rats were euthanized with pentobarbital (100 mg / kg, intraperitoneal) and the airways were washed 5 times with 5 ml of phosphate buffered saline. Harvested cells were stained (Diffquick) and counted to determine overall and differential cellular data. In a typical study, macrophages represent 40-70% of total cells and polymorphonuclear cells represent 30-60% of total cells. Inhibition of neutrophil levels compared to controls not treated with compounds was calculated based on differential counts.

The assay has various conditions such as concentration, pretreatment time, form of the compound (crystalline, amorphous, salt, finely divided form) and wet or dry application of the compound.

Data was obtained at percent inhibition using specific concentrations and pretreatment times. Although a large number of compounds were found to be statistically insignificant (p> 0.05), retesting with increasing concentrations and / or varying pretreatment times resulted in some of these being statistically significant (p <0.05). Is expected to be

Representative compounds of the invention were tested in this assay. Examples 4, 22, 27, 29, 31 (e), 34, 44, 56 (d), 57, 58, 59, 60, 61, 66, 68, 69, 72, 73, 77, 78, 79 ( c), the compounds of 101, 103, 104, 105, 107, 109, 117, 119, 124, 133, 137, 160, 166, 167 and 173 are capable of statistically identifying neutrophils in one or more of the ranges of conditions tested in the assay. Was significantly inhibited.

Examples 23, 24, 25, 28, 32, 67, 70, 71, 76, 95, 99, 100, 102, 112, 113 (b), 115, 118 (b), 120, 122, 125, 129, Compounds of 130, 132, 134, 138, 147, 162, 163 (c), 169, 178, 181 and 185 have been shown to statistically insignificantly inhibit neutrophils in one or more of the ranges of conditions tested in this assay. .

The compounds of Examples 120, 128, 135, 149, 168, 172, 174 and 175 were found to be inactive in this assay.

From traumatic brain injury TNF -α analysis

The assay is to investigate the expression of tumor necrosis factor mRNA in specific brain regions involving experimental lateral latex-impact traumatic brain injury (TBI) in rats. Since TNF-α can induce nerve growth factor (NGF) to stimulate the release of other cytokines from activated astrocytes, these expression changes in post-traumatic TNF-α genes may be altered in both acute and regenerative responses to CNS trauma. Plays an important role. Suitable assays can be found in WO 97/35856, the disclosure of which is incorporated herein by reference above.

IL -b mRNA For CNS  Damage model

This assay identifies local expression of interleukin-1β (IL-1β) mRNA in specific brain regions involving experimental lateral latex-impact traumatic brain injury (TBI) in rats. The results of this analysis indicate that transient expression of IL-1β mRNA after TBI is locally stimulated in certain brain regions. Local changes in these cytokines such as IL-1β play a role in the regeneration sequelae of post-traumatic pathology or brain injury. Suitable assays can be found in WO 97/35856, the disclosure of which is incorporated herein by reference above.

Angiogenesis analysis:

Assays were performed to determine inflammatory angiogenesis, as described in WO 97/32583, the disclosure of which is incorporated herein by reference above, in which cytokine inhibition may result in tissue destruction of excessive or inappropriate proliferation of blood vessels. To show that it will stop.

Renovirus Influenza Analysis:

Renovirus serotype 39 and influenza virus A / PR / 8/34 cell lines were purchased from the American Type Culture Collection (ATCC). BEGM-2 BE cells were purchased from Clonetics Corp. (Bronchoepithelial Growth Medium) was used to cultivate according to the instructions provided by ATCC HELA cell cultures (used for detection and titration of viruses) contained 10% fetal bovine serum, 2 mM 1-glutamine and 10 mM HEPES buffer. Was maintained in Eagle's Minimum Essential Medium (MEM).

A modified method (reported in Subauste et al., Supra) for infecting human bronchial epithelial cells with in vitro virus was used in this study. BEAS-2B cells (2 × 10 ⁵ cells / well) were incubated in collagen-coated wells for 24 hours before being infected with rhinovirus. Renovirus serotype 39 was added to the cell culture and incubated at 34 ° C. for 1 hour, after which the inoculum was replaced with fresh medium and the culture was further incubated at 34 ° C. for 72 hours. Supernatants collected 72 hours after infection were analyzed for cytokine protein concentration by ELISA using a commercially available kit (R & D Systems). In addition, virus yield was determined from the culture supernatant using microtiter analysis in HELA cell cultures (Subauste et al., (1995), supra). In culture treated with a p38 kinase inhibitor, the drug was added 30 minutes before infection. Stock solutions of compounds were prepared in DMSO (10 mM drug) and stored at -20 ° C.

For p38 kinase detection, cultures were incubated in basal medium without growth factors and additives to reduce the endogenous levels of activated p38 kinase. Cells were harvested at various time points after the rhinovirus was added. Detection analysis of tyrosine phosphorylated p38 kinase by immunoblotting was performed according to manufacturer's instructions using commercially available kits (PhosphoPlus p38 MAPK Antibody Kit: New England Biolabs Inc. England BioLabs Inc.).

In some experiments, BEAS-2B cells were infected with influenza virus (A / PR / 8/34 strain) instead of rhinovirus. Culture supernatants were harvested 48 and 72 hours after infection and tested for cytokines by ELISA as described above.

Cells and Viruses : Influenza A / PR / 8/34 subtype H1N1 (VR-95 American Type Culture Collection, Rockville, MD) was propagated in the 10-day-old egg's lumen cavity. After incubation at 37 ° C. and refrigeration at 4 ° C. for 2 h 30 min, ureters were harvested, pooled and centrifuged (1,000 rcf; 15 min; 4 ° C.) to separate cells. The supernatant was aliquoted and stored at -70 ° C. The titer of the virus culture stock solution was 1.0 × 10 ¹⁰ tissue culture infection / ml (TCID ₅₀ ).

Inoculation Procedure : 4-6 week old female Balb / cAnNcrlBr mice were obtained from Charles River (Raleigh, North Carolina, USA). Animals were infected intranasally. Mice were intraperitoneally with ketamine (40 mg / kg; Fort Dodge Labs, Fort Dod, Iowa) and xylazine (5 mg / kg; Miles; Shawnee, Kansas, USA) Anesthetized by injection and inoculated with PR8 of 100 TCID50 diluted in 20 μl PBS. Animals were observed daily for signs of infection. All animal studies were approved by the SmithKline Beecham Pharmaceutical Institutional Animal Care and Use Association.

Viral Titration : At various time points after infection, animals were euthanized and lungs harvested aseptically. Tissues were homogenized in vials containing 1 μm glass beads (Biospec Products, Bartlesville, Oklahoma) and 1 ml of Eagles minimal essential medium. Cell debris was removed by centrifugation at 1,000 rcf for 15 min at 4 ° C. and supernatants were serially diluted in Madin-Darby canine kidney (MDCK) cells. After incubation at 37 ° C. (5% CO ₂ ) for 5 days, 50 μl of 0.5% chick red blood cells per well were added and read for aggregation after 1 hour at room temperature. Virus titers are expressed as 50% tissue culture infection amount (TCID ₅₀ ) calculated by logistic regression.

ELISA : Cytokine levels were measured by quantitative ELISA using commercially available kits. Ear samples were homogenized using a tissue minser in PBS. Cell debris was removed by centrifugation at 14,000 rpm for 5 minutes. Cytokine concentrations and titers were determined as described by the manufacturer; IL-6, IFN-γ and KC (R & D Systems, Minneapolis, Minnesota, USA).

Myeloperoxidase Assay : Myeloperoxidase (MPO) activity is described by Bradley et al. (1982). In sum, hexadecyl trimethyl-ammonium bromide (HTAB) dissolved rabbit cornea in 0.5 m potassium phosphate buffer (JT Baker Scientific, Phillipsburg, NJ) (Sigma Chemical, USA Homogenized in St. Louis, Missouri. After homogenization, the samples were subjected to three cold thaw sonications (Cole-Parmer 8853, Cole-Pharmer, Vernon Hills, Ill.). The suspension was then transparent by centrifugation at 12,500 × g at 40 ° C. for 15 minutes. MPO enzyme activity was determined during the reaction of O-Dianisidine Dihydrochloride (ODI) 0.175 mg / ml (Sigma Chemical, St. Louis, MO) with 0.0002% hydrogen peroxide (Sigma Chemical, St. Louis, MO) It measured by the colorimeter change of absorbance. Measurements were made using a Beckman Du 640 spectrophotometer (Fullerton, CA) equipped with a temperature control device. 50 μl of material to be analyzed was added to 950 μl of ODI and the absorbance change was measured at a wavelength of 460 nm at 25 ° C. for 2 minutes.

Systemic Volume Change Recorder : Influenza virus infected mice were placed in a systemic volume change recorder box with an internal volume of approximately 350 ml. Applying 1 l / min airflow at an angle to the box, measuring and recording flow changes with a Buxco XA data detection and respiration analysis system (Buxco Electronics, Sharon, CT) It was. Animals were acclimated to a volumetric recorder box for 2 minutes before airflow data was recorded. Airway measurements were calculated with enhanced pause (Penh). Penh was previously known as an airway obstruction index, which is associated with increased intrathoracic pressure. The calculation for Penh calculation is as follows: Penh = [(expiration time / relaxation time) −1] × (maximum exhalation flow / maximum inspiratory flow) (where the relaxation time is the time required to discharge Amount).

Arterial Oxygen Saturation Determination : As described using Nonnin veterinary means (Nonin Medical, Inc., Plymouth, Minn.) With a pulse oximeter 8500V with a tongue sensor. Similarly, arterial oxygen saturation% SpO 2 was measured daily (Sidwell et al., 1992 Antimicrobial Agents and Chemotherapy 36: 473-476).

Additional data and analysis variations can be found in PCT / US00 / 25386 (WO 01/19322), filed Sep. 15, 2000, the disclosures of which are incorporated herein by reference in their entirety.

All publications, including patents, patent applications, and the like, mentioned in this specification are incorporated herein by reference as specifically and individually indicated by reference to each individual document as if fully incorporated by reference. do.

The foregoing detailed description discloses the invention completely, including the preferred embodiments. Variations and improvements of the embodiments specifically disclosed herein are included within the scope of the appended claims. It is believed that one skilled in the art can, using the detailed description of the invention, practice the invention to its fullest without further explanation. Accordingly, the examples herein are for illustrative purposes only and should not be regarded as limiting the scope of the invention in any way. Embodiments of the invention claiming exclusive rights and patents are defined as follows.

Claims (94)

A compound of formula (I) or formula (I ') and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof. <Formula I> <Formula Ia> Where G ₁ and G ₂ are independently nitrogen; G ₃ is CH ₂ ; G ₄ is CH; R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ; R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ; R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and; X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ; X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ; R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —; R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring; R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues; R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and; R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues; A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and; R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety; R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen; R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms; R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH); R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form; g is 0 or an integer having a value of 1, 2, 3 or 4; n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10; m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; q is 0, or an integer having a value of 1 to 10; q 'is 0, or an integer having a value of 1 to 6; t is an integer having a value of 2 to 6; v is 0 or an integer having a value of 1 or 2; v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; Z is independently selected at each occurrence from oxygen or sulfur. The compound of claim 1 which is a compound of formula I and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. The compound of claim 1 which is a compound of Formula Ia, and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. 4. The compound of claim 1, wherein R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 ′} ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b which is a compound. The compound of claim 4, wherein R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b . According to claim 1 or 5, R _b is optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted aryl C _{1 - 10} alkyl or an optionally substituted C _{3 -7} cycloalkyl C _{1 A} compound selected from ₁₀ alkyl. The compound of claim 6, wherein R _b is optionally substituted alkyl, optionally substituted heteroaryl, or optionally substituted aryl. 8. Compounds according to claim 7, wherein R _b is propyl, isopropyl, thiazolyl, phenyl or 4-F phenyl. The compound of claim 8, wherein v is 0; R _b is thiazolyl; Z is oxygen; R _{10 '} is hydrogen. According to claim 1 or 9, wherein, R _{1 'is} halogen, C ₁ in each case, _{- 4} alkyl or halo-substituted C _{1 - 4} which will be independently selected from alkyl. The compound of claim 10, wherein R _{1 ′} is independently selected at each occurrence from fluorine, methyl or CF ₃ . 6. The compound of claim 1, wherein X is S (O) _m R _{2. 7} . 6. The compound of claim 1, wherein X is (CH ₂ ) _{n ′} NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ). The compound of claim 13, wherein the R ₄ and R ₁₄ residues are independently at each occurrence a halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; C _{1 - 10} alkyl; Halo-substituted C _{1 - 4} alkyl; SR ₅ ; S (O) R ₅ ; S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; _{NR 4 'C (O) C} 1- 10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano, nitro, C _{1 - 10} alkyl, C _3-7 cycloalkyl or C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Unsubstituted or substituted aryl or aryl-C _{1- 4} alkyl; Unsubstituted or substituted heteroaryl or heteroaryl C _{1 - 4} alkyl; Unsubstituted or substituted heterocyclic or heterocyclic C _{1 - 4} is substituted 1 to 4 times, optionally by alkyl, wherein said aryl, heteroaryl or heterocyclic containing moieties when is halogen, in each case independently; C _{1 - 4} alkyl, hydroxy; A hydroxy-substituted C _{1 - 4} alkyl; C _{1 - 4} alkoxy; S (O) _m alkyl; Amino, mono- or disubstituted with C _{1 - 4} alkyl or amino which is substituted once or twice by CF _3; R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' are cyclized together with the nitrogen to which they are attached, form an oxygen, sulfur or NR To form 5- to 7-membered rings containing additional heteroatoms selected from _{9 '} ; R _j is hydrogen, C ₁ in each case _{- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl C _{1- 4} alkyl, heterocyclic or heterocyclic C _{1 - 4} alkyl residue (hydrogen Except that these residues may be optionally substituted). 15. The method according to claim 14, wherein, R ₄ and R ₁₄ is hydrogen, optionally substituted C _{1 - 10} alkyl, optionally substituted aryl, optionally substituted aryl C ₁₄ alkyl, optionally substituted heterocyclic, optionally substituted heteroaryl when click C _{1- 4} alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C _{1 - 4} which will be independently selected from alkyl. 16. The method of claim 15, C _{1 - 10} alkyl is NR _{4 'R 14'} in each case independently; Halogen, hydroxy, alkoxy, C (O) NR _{4 '} R _14' ; Or a compound that NR ₄ C (O) C _{1- 10} alkyl which is substituted one or more times. The compound of claim 14, wherein X is (CH ₂ ) _{n ′} NR ₄ R ₁₄ ; R ₄ and R ₁₄ heteroaryl C ₁₄ alkyl optionally substituted with one of and; Heteroaryl residues are thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benz A compound selected from imidazolyl and benzothiazolyl. Claim 9 or claim 15 wherein the heteroaryl C _{1 - 4} alkyl moiety is imidazolyl methyl; The other of R ₄ and R ₁₄ is hydrogen; n 'is 0. The compound of claim 14, wherein X is (CH ₂ ) _{n ′} NR ₄ R ₁₄ and one of R ₄ and R ₁₄ is tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imida. Jolly carbonyl, imidazolidinyl, indolinyl, pyrazolyl Jolly carbonyl, pyrazolyl Jolly pyridinyl, piperidinyl, piperazinyl, morpholino, tetrahydro-pyrrole-C _{1 - 4} alkyl, tetrahydropyran-C _{1 - 4} alkyl, tetra tetrahydrofuran _1- C ₄ alkyl, pyrrolidinyl carbonyl C _{1 - 4} alkyl, pyrrolidinyl C _{1 - 4} alkyl, imidazolinyl C _{1 - 4} alkyl, imidazolidinyl C _{1- 4} alkyl, C ₁ indolinyl _{- 4} alkyl, pyrazol Jolly carbonyl C _{1 - 4} alkyl, pyrazol Jolly pyridinyl C _{1 - 4} alkyl, C _{1- 4} alkyl, piperidinyl, piperazinyl, C _{1 - 4} alkyl and morpholino-C _{1 - 4} alkyl selected from an optionally substituted heterocyclic or heterocyclic C _{1 - 4} alkyl moiety of the compound. The method of claim 19, wherein the optionally substituted heterocyclic or heterocyclic C _{1 - 4} alkyl moiety pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolinyl-C _{1 - 4} alkyl, pyrrolidinyl C _{1 - 4} alkyl, piperidinyl C _{1 - 4} alkyl, piperazinyl, C _{1 - 4} alkyl and morpholino-C _{1 -} a compound selected from to ₄ alkyl. The compound of claim 14, wherein X is (CH ₂ ) _{n ′} NR ₄ R ₁₄ and R ₄ and R ₁₄ are cyclized with nitrogen to be optionally substituted selected from pyrrolidine, piperidine, piperazine and morpholine. To form a ring. 15. The compound of claim 14, wherein X is 1,4'-bipipelin-1'yl or 4-methyl-1,4'-bipipelin-1'yl. According to claim 1 or 13, with the R _{2 'moiety} other than hydrogen independently C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 -7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O), cyano , Nitro, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) _{S (O) 2 R 7,} (CR 10 R 20) n NR e R e ', (CR 10 R 20) n NR e R e' C 1 - 4 alkyl, _{NR e R e ', (CR} 10 R 20) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , ( CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) Is optionally substituted 1 to 4 times by C (Z) OR ₇ , Wherein, R _e and R _{e 'is} hydrogen in each case, C _{1 - 4} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, aryl or heteroaryl, C _{1 - 4} alkyl moieties each independently selected from (these moieties, excluding hydrogen are optionally may be substituted), or or R _e and R _{e 'is} an optionally oxygen, together with the nitrogen to which they are attached to a sulfur or NR To form an optionally substituted '4- to 7-membered heterocyclic ring containing an additional heteroatom selected from ₉ ; R ₇ is in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl moiety (moieties thereof Each may be optionally substituted); n is 0, or an integer having a value of 1 to 10. 24. The method of claim 23, X is _{(CH 2) n 'N (} R 2') (R 2 ") , and; R ₂ is an optionally substituted C _{1 - 10} alkyl moiety; an alkyl (CR ₁₀ R _{20) n} the compound to ₄ alkyl NR _e R _{e 'is} substituted by _- NR _e R _e' or _{(CR 10 R 20) n NR} e R e 'C 1. 25. The method of claim 24 wherein, R _e and R _{e 'is} hydrogen or C _{1 in} each case independently of one compound selected from _4-alkyl. The compound of claim 13, wherein the X residue is 3- (diethylamino) propylamino, 3- (dimethylamino) propyl (methyl) amino, 3- (dimethylamino) propyl (methyl) amino, 2- (dimethylamino) ethyl Amino, 1- (methylethyl) amino-propylamino, (1,1-dimethylethyl) aminopropylamino, (1-methylethyl) aminoethylamino, 2- (methylamino) ethylamino, 2-aminoethyl (methyl ) Amino or 2- (dimethylamino) ethyl (methyl) amino. The method of claim 1 wherein, R ₂ are independently C ₁ in each case, _{- 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl alkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O), cyano, nitro, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkylNR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) Optionally substituted one or more times with OR ₇ ; Wherein, R ₇ are in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl residue (these The residues are each independently selected); n is 0, or an integer having a value of 1 to 10. The compound of claim 27, wherein R ₂ is optionally substituted by (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n OR ₆ or (CR ₁₀ R ₂₀ ) _n NR ₄ R ₁₄ . _{1 - 10} alkyl. 4. The compound of claim 1, wherein R ₂ is (CR ₁₀ R ₂₀ ) _{q ′} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) A compound that is _{q ′} C (A ₁ ) (A ₂ ) (A ₃ ). The compound of claim 29, wherein X ₁ is oxygen or N (R ₁₀ ). The compound of claim 29, wherein R ₂ is (CR ₁₀ R ₂₀ ) _{q ′} X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ), wherein A ₁ , A ₂ or A ₃ is At least one is substituted by (CR ₁₀ R ₂₀ ) _n OR ₆ , q is 1 or 2 and q 'is 0. Wherein the first to third according to any one of items, R ₃ is optionally substituted C _{1 - 10} alkyl, C _3-7 cycloalkyl, C _{3 - 7} cycloalkyl-alkyl or aryl compound. 33. The method of claim 32 wherein, R ₃ is a is optionally substituted one or more times, in each case, these residues are all hydrogen, halogen, nitro, in each case C _{1 independently-10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 -7} cycloalkenyl, C _{5 -7} cycloalkenyl C _{1 -10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n SH, (CR 10 R 20) n S (O) m R 7, (CR 10 R 20) n n (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₁₆ R ₂₆ , ( CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C ( Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR ₁₆ R ₂₆ or (CR ₁₀ R ₂₀ ) _n Optionally substituted one or more times with N (R _{10 ′} ) C (Z) OR ₇ ; Wherein, R ₁₆ and R ₂₆ is hydrogen or C ₁ in each case _- more selected from ₄ are each independently selected from alkyl, or R ₁₆ and R ₂₆ is an optionally oxygen, together with the nitrogen to which they are attached to a sulfur or NR _{9 '} To form an unsubstituted or substituted 4- to 7-membered heterocyclic ring containing a heteroatom of; R ₇ is in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl moiety (moieties thereof Each may be optionally substituted); n is 0, or an integer having a value of 1 to 10. 34. The method of claim 33, wherein any of the substituents halogen, in each case, C _{1 - 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n NR 16 R 26 or halo-substituted C _{1 A} compound independently selected from ₁₀ alkyl. 35. The compound of claim 33 or 34, wherein R ₃ is independently at each occurrence phenyl substituted one or more times with fluorine, chlorine, hydroxy, methoxy, amino, methyl or trifluoromethyl. 35. The compound of claim 1 or 34, wherein R ₃ is 2,6-difluorophenyl. The method of claim 1, wherein, R ₃ is halogen, C ₁ in each case independently _{- 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n NR 16 R 26 or halo-substituted C _{1 - 10} alkyl, one to four times by an aryl ring substituted with a; The R _{1 ',} in each case halogen, C _{1 - 4} alkyl or halo - is independently selected from _{4-alkyl-substituted} C _1; g is 0 or 1; R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b ; v is 0; R _b is thiazolyl; Z is oxygen; R _{10 '} is hydrogen; X is (CH ₂ ) _{n '} NR ₄ R ₁₄ ; R ₄ and R ₁₄ is a heteroaryl C ₁₄ alkyl optionally substituted with one of, R ₄ and R ₁₄ is the other of the hydrogen-containing compound. The method of claim 1, N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2, 3-d] pyrimidin-4-yl] -4-methylbenzamide; N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino ] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino ] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; N- (cyclopropylmethyl) -3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-di Hydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; 3- [2-[(2-aminoethyl) (methyl) amino] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -N- (cyclopropylmethyl) -4-methylbenzamide; N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide; N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -2-thiophenecarboxamide; N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -2-thiophenecarboxamide; N- (3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl} -4-methylphenyl) -2-thiophenecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl) -4-methylphenyl] -2-thiophenecarboxamide; N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide; N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide; 6-chloro-N- {3- [8- (2,6-difluorophenyl) -7-oxo-2- (4-piperidinylamino) -7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide; N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -6-chloro-3-pyridinecarboxamide; 6-chloro-N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-pyridinecarboxamide; 6-chloro-N- (3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-pyridinecarboxamide; N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -5-fluoro-4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylpropyl) benzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N-cyclopropyl-4-methylbenzamide; N-cyclopropyl-3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; N-cyclopropyl-3- (8- (2,6-difluorophenyl) -7-oxo-2-{[2- (propylamino) ethyl] amino} -7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (1-methylpropyl) benzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -N- [2- (4-fluorophenyl) ethyl] -4-methylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N- (cyclopropylmethyl) -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (2-phenylethyl) benzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (2-phenylethyl) benzamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methylphenyl} -3-thiophenecarboxamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 -Yl] -4-methylphenyl} -3-thiophenecarboxamide; N- (3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8 -Dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylphenyl) -3-thiophenecarboxamide; N- {3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl] -4-methylphenyl} -3-thiophenecarboxamide; 3- [2-[(2-aminoethyl) (methyl) amino] -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-thiophenecarboxamide; N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-isoquinolinecarboxamide; 6-chloro-N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-pyridinecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-hydroxy-1-naphthalenecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -4-fluoro-1-naphthalenecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -5-methyl-2-pyrazinecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-indole-5-carboxamide; 3-amino-N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7, 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] benzamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-indole-7-carboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2- (3-methylphenyl) acetamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3,4-dimethylbenzamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3-fluoro-4-methylbenzamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -3,5-dihydroxy-4-methylbenzamide; 2- (2,3-difluorophenyl) -N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] Amino} -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] acetamide; 2- (3,5-difluorophenyl) -N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] Amino} -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] acetamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1-methyl-1H-imidazole-4-carboxamide; 4-[(3-{[3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] amino} -3-oxopropyl) amino] -4-oxobutanoic acid; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -1H-pyrazole-3-carboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-thiophenecarboxamide; N- [3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl) -4-methylphenyl] -2-[(2,2,2-trifluoroethyl) oxy] acetamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-propylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (1-methylethyl) benzamide; N-cyclopentyl-3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N- (phenylmethyl) benzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-propylbenzamide; N-cyclopentyl-3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N- (1-methylethyl) benzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N-propylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N-cyclopentyl-4-methylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N- (phenylmethyl) benzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (1-methylethyl) benzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-propylbenzamide; N-cyclopentyl-3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl} -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N- (phenylmethyl) benzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -N- (4-fluorophenyl) -4-methylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N-propylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (1-methylethyl) benzamide; N-cyclobutyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; N-cyclopentyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N- (4-fluorophenyl) -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide; N-cyclopropyl-3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8- Dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; N- (cyclopropylmethyl) -3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7 , 8-dihydropyrido [2,3-d] pyrimidin-4-yl) -4-methylbenzamide; 8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -4- [2-methyl-5- (4-morpholinylcar Carbonyl) phenyl] pyrido [2,3-d] pyrimidin-7 (8H) -one; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -N-heptyl-4-methylbenzamide; N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (3-pyridinylmethyl) benzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (3-phenylpropyl) benzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (2-phenylethyl) benzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N- (phenylmethyl) benzamide; And pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof. The method of claim 1, N- (cyclopropylmethyl) -3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methylbenzamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methylphenyl} -2-thiophenecarboxamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 -Yl] -4-methylphenyl} -2-thiophenecarboxamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4- Il] -4-methylphenyl} -4-fluoro-3-methylbenzamide; N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine-4 -Yl] -4-methylphenyl} -4-fluoro-3-methylbenzamide; 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide; 6-chloro-N- {3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl] -4-methylphenyl} -3-pyridinecarboxamide; 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- N- (4-fluorophenyl) -4-methylbenzamide; 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -N- (4-fluorophenyl) -4-methylbenzamide; N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine- 4-yl] -4-methylbenzamide; N-cyclopropyl-3- [8- (2,6-difluorophenyl) -2- (methylsulfonyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidine -4-yl] -4-methylbenzamide; 3- [8- (2,6-difluoro-phenyl) -2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-propyl-benzamide; 3- [8- (2,6-difluoro-phenyl) -2-methanesulfonyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-propyl-benzamide; 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- 4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; And pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof. The compound according to claim 1, according to formula (I) or (Ia) as defined in any one of Examples. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. An effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or physiology thereof, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, rectal, vaginal or intraperitoneal means of administration A pharmaceutical composition comprising a phase functional derivative together with one or more pharmaceutically acceptable carriers, diluents or excipients. 41. CSBP in a mammal comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a mammal in need thereof, including the prevention of CSBP / RK / p38 kinase mediated disease. / RK / p38 Methods of treatment, including prevention of kinase mediated diseases. 44. The method of claim 43, wherein the CSBP / RK / p38 kinase mediated disease is psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis And other arthritis symptoms, sepsis, sepsis shock, toxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma / obstructive head injury, asthma, adult respiratory distress syndrome, chronic lung inflammatory disease , Chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, heart, brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass graft (CABG) surgery, thrombosis, glomerulonephritis, Chronic renal failure, diabetes, diabetic retinopathy, decreased vision, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcer Benign colitis, neurodegenerative diseases, muscle degeneration, atherosclerosis, diabetic retinopathy, decreased vision, tumor growth and metastasis, angiogenic diseases, influenza-derived pneumonia, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis How to be. An effective amount of a compound according to any one of claims 1 to 40 for a mammal in need of treatment of symptoms of traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms A method of treating traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms in said mammal, comprising administering. 41. A method comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a mammal in need of treatment of asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease or chronic obstructive pulmonary disease (COPD). A method of treating asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease or chronic obstructive pulmonary disease (COPD) in a mammal. Atherosclerosis in a mammal comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a mammal in need thereof for the treatment of atherosclerosis, inflammatory bowel disease, Crohn's disease or ulcerative colitis. How to treat sclerosis, inflammatory bowel disease, Crohn's disease or ulcerative colitis. Effective amounts of humans in need of treatment for a common cold, or respiratory viral infections caused by human enterovirus (HRV), other enteroviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses, or adenoviruses 41. A common cold, or human rhinovirus (HRV), another enterovirus, coronavirus, influenza virus, parainfluenza virus, respiratory tract in said human, comprising administering a compound according to any one of claims 1-40. A method of treating inflammation associated with respiratory viral infections caused by cytofusion virus or adenovirus. 49. The method of claim 48, wherein the respiratory viral infection is aggravating asthma, chronic bronchitis, chronic obstructive pulmonary disease, otitis media or sinusitis or associated with secondary bacterial infection, otitis media, sinusitis or pneumonia. 41. A method of treating inflammation in a mammal comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1-40. A compound of formula (I) or formula (I ') and pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof. <Formula I> <Formula Ia> Where G ₁ and G ₂ are independently nitrogen; G ₃ is CH ₂ ; G ₄ is CH; R ₁ is C (Z) N (R _{10 ′} ) (CR ₁₀ R ₂₀ ) _v R _b ; R _{1 'is} hydrogen, halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R ₂₀ ) is independently selected from _{v ′} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _{v '} OR ₁₃ ; R _b is an optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 - 10} alkyl, cyclic optionally substituted heteroaryl or optionally substituted heterocyclic C _{1 - 10} alkyl; X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ; X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ; R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —; R _q, and R _{q 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 -} independently from (as these moieties are all optionally substituted) _10-alkyl residue _{- 10} alkyl, heteroaryl, heteroaryl C _1-10 alkyl, heterocyclic or heterocyclyl C ₁ Or R _q and R _{q ′} together with the nitrogen to which they are attached form an optionally substituted 5- to 7-membered ring which may contain additional heteroatoms selected from O / N / S; R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues; R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and; R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are independently C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 -1O} alkenyl, C _{2 -1O} alkynyl, C _{3 - 7} cycloalkyl, C _3-7 cycloalkyl C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 -7} cycloalkenyl C _{1- 10} alkyl, halogen, -C (O), cyano, Nitro, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _e' , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n O C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) Or may be optionally substituted 1 to 4 times by OR ₇ ), or Or R _{2 ″} is (CR ₁₀ R ₂₀ ) _t X ₁ (CR ₁₀ R ₂₀ ) _q C (A ₁ ) (A ₂ ) (A ₃ ) residues; A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and; R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety; R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or NR ₉ ; R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms; R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH); R ₆ is hydrogen, C ₁ in each case _{- 10} alkyl, C _{3 - 7} cycloalkyl, heterocyclyl, heterocyclyl C _{1- 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl or heteroaryl C _{1 - 10} alkyl moiety is independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R ₉ is hydrogen, C (Z) R _6, optionally substituted C ₁ in each case _{- 10} alkyl, optionally substituted aryl or optionally substituted aryl C _{1 - 4} are independently selected from alkyl; R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form; g is 0 or an integer having a value of 1, 2, 3 or 4; n is independently selected at each occurrence from 0, or an integer having a value from 1 to 10; n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10; m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; q is 0, or an integer having a value of 1 to 10; q 'is 0, or an integer having a value of 1 to 6; v is 0 or an integer having a value of 1 or 2; v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; s is independently selected from each integer having a value of 1, 2 or 3 in each case; t is an integer having a value of 2 to 6; Z is independently selected at each occurrence from oxygen or sulfur. The compound of claim 51, which is a compound of Formula I, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. The compound of claim 51, which is a compound of Formula la, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Of claim 51 to claim 53 according to any one of items, R _b is an optionally substituted heteroaryl or optionally substituted heteroaryl C _{1 - 10} alkyl. 55. The compound of claim 54, wherein R _b is optionally substituted pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, pyrrolyl C _{1 - 4} alkyl, oxazolyl C _1-4 alkyl, thiazolyl C _{1 - 4} alkyl, isoxazolyl C _{1 - 4} alkyl, isothiazolyl C _{1 - 4} alkyl, imidazolyl C _{1 -4} alkyl, pyrazolyl C _{1 - 4} alkyl, triazolyl C _{1 - 4} alkyl, pyridazinyl C _{1 - 4} alkyl, pyrimidinyl C _{1 - 4} alkyl, pyrazinyl C _{1 - 4} alkyl, benzoxazolyl C _{1 - 4} alkyl, benzimidazolyl C _{1 - 4} alkyl or benzothiazolyl C _{1- 4} alkyl. 55. The compound of claim 51 or 54, wherein R _b is optionally substituted thiazolyl, v is 0, Z is oxygen, and R _{10 '} is hydrogen. The compound will be independently selected from _4-alkyl- claim 51 or claim 54 wherein, R _{1 'is} halogen, C ₁ in each case, _{- 4} alkyl or halo-substituted C _1. The compound of claim 57, wherein R _{1 ′} is independently selected at each occurrence from fluorine, methyl or CF ₃ . The compound of any one of claims 51-53 wherein X is S (O) _m R ₂ . The compound of any one of claims 51-53 wherein X is (CH ₂ ) _n NR ₄ R ₁₄ or (CH ₂ ) _n N (R _{2 ′} ) (R _{2 ″} ). 61. The compound of claim 60, wherein the R ₄ and R ₁₄ residues are independently at each occurrence a halogen; Hydroxy; A hydroxy-substituted C _{1 - 10} alkyl; C _{1 - 10} alkoxy; Halo-substituted C _{1 - 10} alkoxy; C _{1 - 10} alkyl; Halo-substituted C _{1 - 4} alkyl; SR ₅ ; S (O) R ₅ ; S (O) ₂ R ₅ ; C (O) R _j ; C (O) OR _j ; C (O) NR _{4 '} R _14' ; NR _{4 ′} C (O) C _1-10 alkyl; NR _{4 '} C (O) aryl; NR _{4 '} R _14' ; Cyano, nitro, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl or C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl; Halo-substituted C _{1 - 10} alkyl; Unsubstituted or substituted aryl or aryl-C _{1- 4} alkyl; Unsubstituted or substituted heteroaryl or heteroaryl C _{1 - 4} alkyl; Unsubstituted or substituted heterocyclic or heterocyclic C _{1 - 4} is substituted 1 to 4 times, optionally by alkyl, wherein said aryl, heteroaryl or heterocyclic containing moieties when is halogen, in each case independently; C _{1 - 4} alkyl; Hydroxy; A hydroxy-substituted C _{1 - 4} alkyl; C _{1 - 4} alkoxy; S (O) _m alkyl; Amino, mono- or disubstituted with C _{1 - 4} alkyl or amino which is substituted once or twice by CF _3; R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' are cyclized together with the nitrogen to which they are attached, form an oxygen, sulfur or NR To form 5- to 7-membered rings containing additional heteroatoms selected from _{9 '} ; R _j is hydrogen, C ₁ in each case _{- 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl C _{1- 4} alkyl, heterocyclic or heterocyclic C _{1 - 4} alkyl residue (hydrogen Except that these residues may be optionally substituted). 62. The method of claim 61, wherein, R ₄ and R ₁₄ is hydrogen, optionally substituted C _{1 - 10} alkyl, optionally substituted aryl, optionally substituted aryl C ₁₄ alkyl, optionally substituted heterocyclic, optionally substituted heteroaryl when click C _{1- 4} alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C _{1 - 4} which will be independently selected from alkyl. 63. The method of claim 62, C _{1 - 10} alkyl is NR _{4 'R 14'} in each case independently; Halogen, hydroxy, _{alkoxy, C (O) NR 4 '} R 14' or _{NR 4 'C (O) C} 1- ₁₀ alkyl being optionally substituted once or more compounds. 61. The compound of claim 60, wherein X is (CH ₂ ) _{n '} NR ₄ R ₁₄ ; R ₄ and R ₁₄ heteroaryl C ₁₄ alkyl optionally substituted with one of and; Heteroaryl residues are thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benz A compound selected from imidazolyl and benzothiazolyl. The method of claim 64 wherein heteroaryl C _{1 - 4} alkyl moiety is imidazolyl methyl; The other of R ₄ and R ₁₄ is hydrogen; n is 0. 61. The compound of claim 60, wherein X is (CH ₂ ) _n NR ₄ R ₁₄ and one of R ₄ and R ₁₄ is tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazoli carbonyl, imidazolidinyl, indolinyl, pyrazolyl Jolly carbonyl, pyrazolyl Jolly pyridinyl, piperidinyl, piperazinyl, morpholino, tetrahydro-pyrrole-C _{1 - 4} alkyl, tetrahydropyran-C _{1 - 4} alkyl, tetrahydronaphthalene furan-C _1-4 alkyl, pyrrolidinyl carbonyl C _{1 - 4} alkyl, pyrrolidinyl C _{1 - 4} alkyl, imidazolinyl C _{1 - 4} alkyl, C _{1- 4} alkyl, imidazolidinyl, indolinyl C _{1 - 4} alkyl, pyrazol Jolly carbonyl C _{1 - 4} alkyl, pyrazol Jolly pyridinyl C _{1 - 4} alkyl, piperidinyl C _1-4 alkyl, piperazinyl C _{1 - 4} alkyl and morpholino-C _{1 - 4} alkyl optionally selected from substituted heterocyclic or heterocyclic C _{1 - 4} alkyl moiety of the compound. 67. The method of claim 66, wherein the optionally substituted heterocyclic or heterocyclic C _{1 - 4} alkyl residue is pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolinyl-C _{1 -4} alkyl, pyrrolidinyl C _{1 - 4} alkyl, piperidinyl C _{1 - 4} alkyl, piperazinyl, C _{1 - 4} alkyl and morpholino-C _{1 -} a compound selected from to ₄ alkyl. The compound of claim 60, wherein X is (CH ₂ ) _{n ′} NR ₄ R ₁₄ and R ₄ and R ₁₄ are cyclized with nitrogen to be optionally substituted selected from pyrrolidine, piperidine, piperazine and morpholine. To form a ring. 55. The compound of any one of claims 51-53, wherein X is 1,4'-bipipelin-1'yl or 4-methyl-1,4'-bipipelin-1'yl. The method of claim 60, wherein, X is _{(CH 2) n N (R} 2 ') (R 2 ") , and; R _2' is optionally substituted with C _{1 -} and _10-alkyl residue, an alkyl (CR ₁₀ R _{20) n} the compound to ₄ alkyl NR _e R _{e 'is} substituted by _- NR _e R _e' or _{(CR 10 R 20) n NR} e R e 'C 1. The compound will be independently selected from _4-alkyl- according to claim 70 wherein, R _e and R _{e 'is} hydrogen or an optionally substituted C ₁ in each case. The compound of any one of claims 51-53, wherein X is 3- (diethylamino) propylamino, 3- (dimethylamino) propyl (methyl) amino, 3- (dimethylamino) propyl (methyl) amino, 2- (dimethylamino) ethylamino, 1- (methylethyl) amino-propylamino, (1,1-dimethylethyl) aminopropylamino, (1-methylethyl) aminoethylamino, 2- (methylamino) ethylamino , 2-aminoethyl (methyl) amino or 2- (dimethylamino) ethyl (methyl) amino. The method of claim 51 wherein, R ₂ are independently in each case C _{1 - 10} alkyl, halo-substituted C _{1 -10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl alkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, halogen, -C (O), cyano, nitro, (CR ₁₀ R ₂₀ ) _n OR ₆ , (CR ₁₀ R ₂₀ ) _n SH, (CR ₁₀ R ₂₀ ) _n S (O) _m R ₇ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n NR _e R _e' C _1-4 alkylNR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (= N (R _10' )) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n C (= NOR ₆ ) NR _e R _e' , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _e R _{e '} , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) NR _e R _{e '} or (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (Z) Optionally substituted one or more times with OR ₇ ; Wherein, R ₇ are in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl residue (these The residues are each independently selected); n is 0, or an integer having a value of 1 to 10. The compound of claim 73, wherein R ₂ is optionally substituted by (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n OR ₆ or (CR ₁₀ R ₂₀ ) _n NR ₄ R ₁₄ . _{1 - 10} alkyl. Of claim 51 to claim 53 according to any one of items, R ₃ is optionally substituted C _{1 - 10} alkyl, C _3-7 cycloalkyl, C _{3 - 7} cycloalkyl-alkyl or aryl compound. The method of claim 75 wherein, R ₃ a is independently optionally substituted one or more times, in each case, these residues are all independently hydrogen, halogen, nitro, in each case, C _{1 - 10} alkyl, halo-substituted C _{1 - 10} alkyl, C _{2 - 10} alkenyl, C _{2 - 10} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 -7} cycloalkenyl, C _{5 -7} cycloalkyl alkenyl C _{1 -10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n SH, (CR 10 R 20) n S (O) m R 7, (CR 10 R 20) n n (R _{10 '} ) S (O) ₂ R ₇ , (CR ₁₀ R ₂₀ ) _n NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n CN, (CR ₁₀ R ₂₀ ) _n S (O) ₂ NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) OR ₆ , (CR ₁₀ R ₂₀ ) _n C (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) R ₆ , (CR ₁₀ R ₂₀ ) _n N (R _10' ) C (= N (R _{10 '} )) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₁₆ R ₂₆ , (CR ₁₀ R ₂₀ ) _n N (R _{10 '} ) C (Z) NR ₁₆ R ₂₆ or (CR ₁₀ R ₂₀ ) _n is optionally substituted one or more times with N (R _{10 ′} ) C (Z) OR ₇ ; Wherein, R ₁₆ and R ₂₆ is hydrogen or C ₁ in each case _- more selected from ₄ are each independently selected from alkyl, or R ₁₆ and R ₂₆ is an optionally oxygen, together with the nitrogen to which they are attached to a sulfur or NR _{9 '} To form an unsubstituted or substituted 4- to 7-membered heterocyclic ring containing a heteroatom of; R ₇ is in each case C _{1 - 6} alkyl, aryl, aryl C _{1 - 6} alkyl, heterocyclic, heterocyclyl C _{1- 6} alkyl, heteroaryl or heteroaryl-C _{1 - 6} alkyl moiety (moieties thereof Each may be optionally substituted); n is 0, or an integer having a value of 1 to 10. The method of claim 76, wherein any of the substituents halogen, C _{1 -} from _{10 alkyl-10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n NR 16 R 26 or halo-substituted C ₁ Independently selected compound. The compound of claim 51, wherein R ₃ is independently at each occurrence a phenyl ring substituted one or more times with fluorine, chlorine, hydroxy, methoxy, amino, methyl or trifluoromethyl. 79. The compound of claim 78, wherein R ₃ is a phenyl ring substituted one or more times with fluorine or methyl. 80. The compound of claim 79, wherein R ₃ is 2,6-difluorophenyl. The method of claim 51 wherein, R ₃ is halogen, C ₁ in each case independently _{- 10 alkyl, (CR 10 R 20) n} OR 6, (CR 10 R 20) n NR 16 R 26 or halo-substituted C _{1 - 10} alkyl, one to four times by an aryl ring substituted with a; The R _{1 ',} in each case halogen, C _{1 - 4} alkyl or halo - is independently selected from _{4-alkyl-substituted} C _1; g is 0, 1 or 2; v is 0; R _b is thiazolyl; Z is oxygen; R _{10 '} is hydrogen. The method of claim 51, 3- (8- (2,6-difluorophenyl) -2-{[2- (methylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- {8- (2,6-difluorophenyl) -7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl) amino] -7,8-dihydro Pyrido [2,3-d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [2- (4-amino-1-piperidinyl) -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrid Midin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[(1H-imidazol-2-ylmethyl) amino] -7-oxo-7,8-dihydropyrido [2,3- d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2- (methylthio) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl]- 4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2- (methylsulfinyl) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2-hydroxy-1- (hydroxymethyl) ethyl] amino} -7-oxo-7,8-dihydropyrido [ 2,3-d] pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2-({3-[(1-methylethyl) amino] propyl} amino) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2-({3-[(1,1-dimethylethyl) amino] propyl} amino) -7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [8- (2,6-difluorophenyl) -2-({2-[(1-methylethyl) amino] ethyl} amino) -7-oxo-7,8-dihydropyrido [2 , 3-d] pyrimidin-4-yl] -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- {8- (2,6-difluorophenyl) -2-[[3- (dimethylamino) propyl] (methyl) amino] -7-oxo-7,8-dihydropyrido [2,3 -d] pyrimidin-4-yl} -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- (8- (2,6-difluorophenyl) -2-{[2- (dimethylamino) ethyl] amino} -7-oxo-7,8-dihydropyrido [2,3-d] Pyrimidin-4-yl) -4-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N-[(5-methyl-2-furanyl) methyl] benzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -4-methyl-N- (2-thienyl-methyl) benzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N- [2- (1H-imidazol-4-yl) ethyl] -4-methylbenzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -2-methyl-N-1,3-thiazol-2-ylbenzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -5-fluoro-4-methyl-N-1,3-thiazol-2-ylbenzamide; 4- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-1,3-thiazol-2-ylbenzamide; 3- [2-{[3- (diethylamino) propyl] amino} -8- (2,6-difluorophenyl) -7-oxo-7,8-dihydropyrido [2,3-d ] Pyrimidin-4-yl] -N-1,3-thiazol-2-ylbenzamide; Or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. A pharmaceutical composition comprising an effective amount of a compound according to claim 51, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. 83. CSBP in a mammal comprising administering an effective amount of a compound according to any one of claims 51 to 82 to a mammal in need thereof, including the prevention of CSBP / RK / p38 kinase mediated disease / RK / p38 Methods of treatment, including prevention of kinase mediated diseases. 85. The method according to claim 84, wherein the CSBP / RK / p38 kinase mediated disease is psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis Symptoms, sepsis, sepsis shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma / obstructive head injury, asthma, adult respiratory distress syndrome, chronic lung inflammatory disease, chronic obstructive Lung disease (COPD), silicosis, pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, heart, brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass graft (CABG) surgery, thrombosis, glomerulonephritis, chronic renal failure, Diabetes, diabetic retinopathy, poor vision, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nerve Planet disease, muscle degeneration, atherosclerosis, diabetic retinopathy, visual impairment, tumor growth and metastasis, angiogenic disease, influenza-derived pneumonia, eczema, contact dermatitis, psoriasis, solar images, or conjunctivitis way. An effective amount of a compound according to any one of claims 51 to 82 for a mammal in need of treatment of symptoms of traumatic arthritis, rubella arthritis, acute synoviitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms A method of treating traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis symptoms in said mammal, comprising administering. 83. A method comprising administering an effective amount of a compound according to any one of claims 51 to 82 to a mammal in need of treatment of asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease or chronic obstructive pulmonary disease (COPD). A method of treating asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease or chronic obstructive pulmonary disease (COPD) in a mammal. 82. An atherosclerotic art in a mammal comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 51 to 82 for the treatment of atherosclerosis, inflammatory bowel disease, Crohn's disease or ulcerative colitis. How to treat sclerosis, inflammatory bowel disease, Crohn's disease or ulcerative colitis. 83. A method of treating inflammation in a mammal comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 51-82. A compound of formula II or IIa, and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. <Formula II> <Formula IIa> Where G ₁ and G ₂ are independently nitrogen; G ₃ is CH ₂ ; G ₄ is CH; R ₁ is C (Z) N (R _{10 '} ) (CR ₁₀ R ₂₀ ) _v R _b , C (Z) O (CR ₁₀ R ₂₀ ) _v R _b , N (R _10' ) C (Z) (CR ₁₀ R ₂₀ ) _v R _b , N (R _{10 '} ) C (Z) N (R _10' ) (CR ₁₀ R ₂₀ ) _v R _b or N (R _{10 '} ) OC (Z) (CR ₁₀ R ₂₀ ) _v R _b ; R _{1 'is} halogen, C ₁ in each case _{- 4} alkyl, halo-substituted C _{1 - 4} alkyl, cyano, _{nitro, (CR 10 R 20) v} ' NR d R d ', (CR 10 R 20 ) _{v '} C (O) R ₁₂ , SR ₅ , S (O) R ₅ , S (O) ₂ R ₅ or (CR ₁₀ R ₂₀ ) _v' OR ₁₃ ; R _b is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all optionally may be substituted), and; X is R ₂ , OR _{2 '} , S (O) _m R _2' , (CH ₂ ) _{n '} N (R _10' ) S (O) _m R _{2 '} , (CH ₂ ) _n' N (R _{10 '} ) C (O) R _{2 '} , (CH ₂ ) _n' NR ₄ R ₁₄ , (CH ₂ ) _{n '} N (R _2' ) (R _{2 "} ) or N (R _{10 '} ) R _h NH-C ( = N-CN) NR _q R _{q '} ; X ₁ is N (R ₁₁ ), O, S (O) _m or CR ₁₀ R ₂₀ ; R _h is an optionally substituted C _{1 - 10 alkyl, -CH 2 -C (O) -CH} 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C (O) N (R _{10 '} ) CH ₂ -CH _2- , -CH ₂ -N (R _10' ) C (O) CH _2- , -CH ₂ -CH (OR _{10 '} ) -CH _2- , -CH ₂ -C (O) O—CH ₂ —CH ₂ — or —CH ₂ —CH ₂ —OC (O) CH ₂ —; R _q, and R _{q 'are} in each case hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 -10} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are all Optionally substituted) or R _q and R _{q ′} are optionally substituted 5- to 7-membered which, together with the nitrogen to which they are attached, may contain additional heteroatoms selected from oxygen, nitrogen or sulfur To form a heterocyclic ring; R ₂ is hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic, or heterocyclyl-C _{1 - 10} alkyl moiety, or (these moieties, excluding hydrogen are each optionally may be substituted), or R ₂ is _{(CR 10 R 20) q '} X 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) or (CR ₁₀ R ₂₀ ) _{q '} C (A ₁ ) (A ₂ ) (A ₃ ) residues; R _{2 'is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} alkyl residue (these moieties, excluding hydrogen are each optionally may be substituted), and; R _{2 "is} hydrogen, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic or heterocyclyl-C _{1 - 10} (subject to these moieties, excluding hydrogen are optionally substituted) alkyl moieties, or is R _{2 "is (CR 10 R 20) t X} 1 (CR 10 R 20) q C (a 1 ) (A ₂ ) (A ₃ ) residues; A ₁ is optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₂ is an optionally substituted C _{1 - 10} alkyl, heterocyclic, heterocyclic C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, aryl or aryl-C _{1 - 10} alkyl; A ₃ is hydrogen or an optionally substituted C _{1 - 10} alkyl, and; R ₃ is C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C _{1 - 10} alkyl, aryl, aryl C _{1 - 10} alkyl, heteroaryl, heteroaryl-C _{1 - 10} alkyl, heterocyclic click or heterocyclyl C _{1 - 10} (that these moieties may be optionally substituted, respectively) alkyl moiety; R ₄ and R ₁₄ is hydrogen in each case, C ₁₄ alkyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl, C ₁₄ alkyl, aryl, C ₁₄ alkyl, heterocyclic, heterocyclic C ₁₄ alkyl, heteroaryl or heteroaryl C ₁₄ alkyl residues are each independently selected from (these moieties, excluding hydrogen are each optionally may be substituted), or R ₄ and R ₁₄ to which they are attached are Together with the nitrogen to form an optionally substituted 4- to 7-membered heterocyclic ring optionally containing further heteroatoms selected from oxygen, sulfur or nitrogen; R _{4 'and} R _14' are either each independently selected from hydrogen or C ₁₄ alkyl, in each case, or R _{4 'and} R _14' is further selected from heteroaryl optionally NR _{9 'together} with the nitrogen to which they are attached To form 5- to 7-membered heterocyclic rings containing atoms; R ₅ is hydrogen, C ₁₄ alkyl, C ₂ in each case _{- 4} alkenyl, C _{2 - 4} alkynyl or NR ₄ are independently selected from the _{'R 14'} (residues SR ₅ is SNR _{4 'R 14 '} , Except where S (O) ₂ R ₅ is SO ₂ H and S (O) R ₅ is SOH); R _{9 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₀ and R ₂₀ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R _{10 'is} hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₁ is hydrogen or C ₁ in each case _- is independently selected from _4-alkyl; R ₁₂ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R ₁₃ is hydrogen in each case, C _{1 - 4} alkyl, halo-substituted C _{1 - 4} alkyl, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, C _{3 - 7} cycloalkyl, C _{3 - 7} cycloalkyl C _{1 - 4} alkyl, C _{5 - 7} cycloalkenyl, C _{5 - 7} cycloalkenyl C _{1 - 4} alkyl, aryl, aryl C _{1 - 4} alkyl, heteroaryl, heteroaryl-C _{1 - 4} alkyl, heteroaryl, heterocyclyl or heterocyclyl-C _{1- 4} alkyl moiety independently selected from (these moieties, excluding hydrogen are each optionally may be substituted); R _d and R _{d 'is} hydrogen, C _{1 -} respectively from the _four alkyl residues (these moieties, excluding hydrogen are that each may be optionally substituted) _{- 4} alkyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl, C ₁ Are independently selected or R _d and R _{d '} together with the nitrogen to which they are attached optionally an optionally substituted 5- or 6-membered heterocyclic ring containing an additional heteroatom selected from oxygen, sulfur or NR _9' To form; g is 0 or an integer having a value of 1, 2, 3 or 4; n 'is independently selected at each occurrence from 0, or an integer having a value from 1 to 10; m is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; q is 0, or an integer having a value of 1 to 10; q 'is 0, or an integer having a value of 1 to 6; t is an integer having a value of 2 to 6; v is 0 or an integer having a value of 1 or 2; v 'is independently selected at each occurrence from 0, or an integer having a value of 1 or 2; Z is independently selected at each occurrence from oxygen or sulfur. A pharmaceutical composition comprising an effective amount of a compound according to claim 90, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. CSBP / RK / p38 kinase mediated disease in a mammal comprising administering an effective amount of a compound according to claim 90 to a mammal in need thereof, including the prevention of CSBP / RK / p38 kinase mediated disease. Methods of treatment, including prevention of. 92. The method of claim 92, wherein the CSBP / RK / p38 kinase mediated disease is psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis Symptoms, sepsis, sepsis shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma / obstructive head injury, asthma, adult respiratory distress syndrome, chronic lung inflammatory disease, chronic obstructive Lung disease (COPD), silicosis, pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, heart, brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass graft (CABG) surgery, thrombosis, glomerulonephritis, chronic renal failure, Diabetes, diabetic retinopathy, poor vision, atherosclerosis, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease , Ulcerative colitis, neurodegenerative diseases, muscle degeneration, atherosclerosis, diabetic retinopathy, decreased vision, tumor growth and metastasis, angiogenic diseases, influenza-derived pneumonia, eczema, contact dermatitis, psoriasis, sunburn Or conjunctivitis. 93. A method of treating inflammation in a mammal comprising administering to the mammal in need thereof an effective amount of a compound according to any one of claims 90.